A Phase I / 2, Multicenter, Open-label, Single-dose, Dose-ranging Study to Assess the Safety and Tolerability of SB-318, a rAAV2/6-based Gene Transfer in Subjects With Mucopolysaccharidosis I (MPS I)
Phase: PHASE1
Conditions: MPS I
Sponsor: Sangamo Therapeutics

Pr ot o c ol, A m e n d m e nt 7  
Pr ot o c ol N u m b er:  
S B -3 1 8 -1 5 0 2  
Titl e:  
 A P h a s e 1/ 2, M ulti c e nt er, O p e n -L a b el, Si n gl e -D o s e, D o s e -R a n gi n g 
St u d y t o A s s e s s t h e S af et y a n d T ol er a bilit y of S B -3 1 8, a r A A V 2/ 6 -
b a s e d G e n e Tr a n sf er i n S u bj e ct s wit h M u c o p ol y s a c c h ari d o si s I ( M P S I)  
D at e of Pr ot o c ol:  
1 2 D e c 2 0 1 9  
B B -I N D: 
1 6 8 2 1  
E u dr a C T:  
2 0 1 8 -0 0 0 2 0 6 -2 8  
N C T:  
N C T 0 2 7 0 2 1 1 5  
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 1  of 8 6  
 
 
 
 
Cli nic al St u d y Pr ot oc ol  
 
A P h ase 1/ 2 , M ultice nter, O pe n -L a bel, Si n gle -D ose, D ose -R a n gi n g 
St u d y t o A ssess t he S afet y a n d T oler a bilit y  of S B -3 1 8, a 
r A A V 2/ 6 -b ase d Ge ne Tr a nsfer i n Su bjects wit h 
M uc o p ol ys acc h ari d osis I ( M P S  I) 
 
 
Pr ot oc ol N u m ber:  S B -3 1 8 -1 5 0 2  
B B -I N D: 1 6 8 2 1  
E u dr a C T:  2 0 1 8 -0 0 0 2 0 6 -2 8  
S p o ns or:  Sa n ga m o  T hera p e utics , I nc. 
7 0 0 0 Mari na Bl v d.  
Bris ba ne , C A 9 4 0 0 5  
P h o ne:  ( 5 1 0) 9 7 0-6 0 0 0  
Fa x:  ( 5 1 0) 9 7 0-6 0 0 9  
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 2  of 8 6  
Cli nic al St u d y Pr ot oc ol  
 
A P h ase 1/ 2 , M ultice nter, O pe n-L a bel, Si n gle -D ose, D ose -R a n gi n g 
St u d y t o Assess t he S afet y a n d T oler a bilit y of S B -3 1 8, a 
r A A V 2/ 6 -b ase d Ge ne Tr a nsfer i n S u bjects wit h 
M uc o p ol ys acc h ari d osis I ( M P S I)  
 
Pr ot oc ol N u m ber:  S B -3 1 8 -1 5 0 2  
B B -I N D: 1 6 8 2 1  
E u dr a C T:  2 0 1 8 -0 0 0 2 0 6 -2 8  
S p o ns or:  Sa n ga m o  T hera p e utics , I nc. 
7 0 0 0 Mari na Bl v d.  
Bris ba ne , C A 9 4 0 0 5  
P h o ne:  ( 5 1 0) 9 7 0-6 0 0 0  
Fa x:  ( 5 1 0) 9 7 0-6 0 0 9  
Me dic al M o nit or:  
 
West o n Miller , M. D. 
P h o ne: ( 5 1 0) 3 0 7 -7 2 9 6   
Fa x: ( 5 1 0) 3 2 3 -7 5 1 9  
w miller @sa n ga m o.c o m  
Ori gi n al Versi o n:  Dece m b er  1 7 , 2 0 1 5  
A me n d me nt 1:  Oct o ber 1 7, 2 0 1 6  
A me n d me nt 2:  Oct o ber  4,  2 0 1 7  
A me n d me nt 3:  Marc h 7,  2 0 1 8  
A me n d me nt 4:  A pril 2 5, 2 0 1 8  
A me n d me nt 5:  J ul y 2 4, 2 0 1 8 
A me n d me nt 6:  Dece m b er 3,  2 0 1 8  
A me n d me nt 7:  Dece m b er  1 2 , 2 0 1 9 
 
P R O P E R T Y O F S A N G A M O T H E R A P E U TI C S , I N C. 
C o nfi de nti al a n d Pr o priet ar y  
T his d oc u me nt c o ntai ns c o nfi de ntial a n d pr o priet ar y i nf or mati o n. It is i nte n de d s olel y f or t he use 
of t he i n vesti gat or, c o-i n vesti gat ors, staff, a p pr o priate i nstit uti o nal re vie w b oar ds or et hical 
c o m mittees, a n d ot her re q uire d re g ulat or y b o dies. T he i nf or m ati o n i n t his d oc u me nt ma y n ot be 
discl ose d, di v ul ge d, or p u blis he d e xter nall y wit h o ut writte n a p pr o val fr o m S a n ga m o T hera pe utics, 
I n c. 
 
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, t he I nter nati o nal C ou ncil  fo r 
Har m o nisati o n (I C H) G ui deli nes, G o o d Cli nical Practice s a n d a p plica ble re g ulat or y re q uire me nt s, 
i ncl u di n g t he U. S. C o de of Fe d eral Re g ulati o ns.

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 4  of 8 6  
 
S a n g a m o T her a pe utics , I nc. 
 
 
I n vesti g at or A gree me nt P a ge  
 
 
 
Pr ot oc ol N u m ber:  S B -3 1 8 -1 5 0 2  
B B -I N D: 1 6 8 2 1  
E u dr a C T:  2 0 1 8 -0 0 0 2 0 6 -2 8  
Pr ot oc ol Title:  A 
P hase 
1/ 2 , 
Multice nter, 
O pe n -L a bel, 
Si n gle -D ose , D ose-R a n gi n g St u d y t o Assess 
t he Safet y a n d T olera bilit y of S B-3 1 8, a 
r A A V 2/ 6-bas e d 
Ge n e Tra nsfer i n S u bjects 
wit h M uc o p ol ysacc hari d osis I  ( M P S I) 
 
 
 
I ha v e rea d all pa ges of t his cli nical st u d y pr ot oc ol f or w hic h Sa n ga m o T hera pe utics, I n c. is t he 
S p o ns or. I a gree t o c o n d u ct t he st u d y as o utli ne d i n t he pr ot oc ol , a n d t o c o m pl y wit h all ter ms a n d 
c o n diti o ns set o ut t herei n. I c o nfir m t hat I will c o n d uct t he st u d y i n acc or da nce wit h I C H g ui d eli nes 
a n d a p plica ble l oc al re g ulati o ns. I will e ns ure t hat s u b -i n vesti gat or(s) a n d ot her rele va nt me m bers 
of m y staff ha ve access t o c o p ies of t his pr ot oc ol a n d t he I C H  g ui deli nes t o e na ble t he m t o w or k 
i n acc or da nce wit h t he pr o visi o ns of t hese d oc u me nts.  
 
 
 
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I n v esti gat or Si g nat ure  
  
 
 
 
 
 
Date  
 
 
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I n v esti gat or Pri nte d Na m e 
  
 
 
 
 
 
 
 
 
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Site Na me  
 
 
  
 
 
 
 
 
 
 
 
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Site A d dress  
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 5  of 8 6  
T A B L E O F C O N T E N T S  
1  
I N T R O D U C TI O N ............................................................................................................... 2 3  
1. 1  
M U C O P O L Y S A C C H A RI D O SI S I ........................................................................................ 2 3  
1. 2  
D E V E L O P M E N T O F Z I N C F I N G E R N U C L E A S E S F O R G E N O M E E DI TI N G  ............................ 2 4  
1. 3  
P H A R M A C O L O G Y S T U DI E S WI T H S B -3 1 8  ...................................................................... 2 5  
1. 3. 1  I n Vitr o St u dies  ..........................................................................................................2 5  
1. 3. 2  I n Viv o St u dies  ...........................................................................................................2 5  
1. 4  
C LI NI C A L E X P E RI E N C E WI T H Z I N C F I N G E R N U C L E A S E S  ................................................ 2 8  
1. 5  
D O S E JU S TI FI C A TI O N  ..................................................................................................... 2 9  
1. 6  
T A R G E T E D P A TI E N T P O P U L A TI O N  ................................................................................. 3 0  
1. 7  
R I S K B E N E FI T A S S E S S M E N T A N D S T U D Y H Y P O T H E SI S  .................................................. 3 0  
2  
S T U D Y O B J E C TI V E S  ....................................................................................................... 3 2  
2. 1  
P RI M A R Y O BJ E C TI V E S  ................................................................................................... 3 2  
2. 2  
 S E C O N D A R Y O BJ E C TI V E S  ............................................................................................. 3 2  
2. 3  
E X P L O R A T O R Y O BJ E C TI V E S  .......................................................................................... 3 2  
3  
S T U D Y D E SI G N  ................................................................................................................. 3 3  
3. 1  
O V E R VI E W  .................................................................................................................... 3 3  
3. 2  
N U M B E R O F S U BJ E C T S  .................................................................................................. 3 3  
3. 3  
D O S E  ............................................................................................................................. 3 3  
3. 4  
S T U D Y D U R A TI O N  ......................................................................................................... 3 3  
3. 5  
S T U D Y S C H E D U L E  ......................................................................................................... 3 4  
4  
S U B J E C T S E L E C TI O N  ..................................................................................................... 3 7  
4. 1  
IN C L U SI O N C RI T E RI A  .................................................................................................... 3 7  
4. 2  
E X C L U SI O N C RI T E RI A  ................................................................................................... 3 7  
5  
I N F O R M E D C O N S E N T ..................................................................................................... 3 9  
6  
S T U D Y M E T H O D O L O G Y ................................................................................................ 4 0  
6. 1  
S C R E E NI N G  ................................................................................................................... 4 0  
6. 2  
S U BJ E C T E N R O L L M E N T  ................................................................................................. 4 1  
6. 3  
B A S E LI N E  ...................................................................................................................... 4 1  
6. 4  
D A Y 0  ( S B-3 1 8  IN F U SI O N ) ............................................................................................ 4 2  
6. 5  
D A Y 1  ........................................................................................................................... 4 3  
6. 6  
D A Y 7  ( +/- 1  D A Y ) ......................................................................................................... 4 3  
6. 7  
W
E E K S 2,  4,  6,  A N D 8  ( +/- 2  D A Y S ) ................................................................................ 4 3  
6. 8  
W
E E K S 1 2,  1 6,  2 0 , 2 4,  2 8,  3 2,  3 6,  4 0,  4 4,  4 8,  A N D 5 2  ( +/- 1  W E E K ) ............................... 4 4  
6. 9  
M O N T H S 1 5,  1 8,  2 1,  2 4,  2 7,  3 0,  3 3,  A N D 3 6/ E N D O F S T U D Y ( +/-1  M O N T H ) ................... 4 5  
6. 1 0  E A R L Y T E R MI N A TI O N  ................................................................................................... 4 6  
6. 1 1  E R T  W
I T H D R A W A L (A N Y TI M E A F T E R W
E E K 1 2)  ......................................................... 4 7  
6. 1 2  E R T  W
I TH D R A W A L M O NI T O RI N G ( E R T W
I T H D R A W A L W
E E K S 1,  2,  3,  4,  6,  8,  1 0,  A N D 1 2  
[ +/- 2  D A Y S ]) ................................................................................................................. 4 8  
6. 1 3   E R T  W
I T H D R A W A L F O L L O W -U P (U P T O 1 2  W E E K S  P O S T -E R T  W
I T H D R A W A L VI SI T) ... 4 8  
7  
I N V E S TI G A TI O N A L P R O D U C T A N D O T H E R S T U D Y M E DI C A TI O N S  .............. 4 9  

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 6  of 8 6  
7. 1  
S B -3 1 8  ......................................................................................................................... 4 9  
7. 1. 1   I n v e nt or y, St ora ge, a n d Ha n dli n g of t he Dr u g Pr o d uct ............................................4 9  
7. 1. 2  S B -3 1 8 A d mi nistrati o n  ..............................................................................................4 9  
7. 1. 3  Preca uti o ns  .................................................................................................................5 0  
7. 1. 4  D ose M o dificati o ns  ....................................................................................................5 0  
7. 2  
C O N C O MI T A N T M E DI C A TI O N A N D S U P P O R TI V E C A R E  .................................................. 5 0  
8  
S A F E T Y A N D P O T E N TI A L RI S K S  ................................................................................ 5 1  
8. 1  
S B -3 1 8  ......................................................................................................................... 5 1  
8. 1. 1  P ote ntial O n -Tar get Effect o n Al b u mi n  .....................................................................5 2  
8. 1. 2  P ote ntia l Off-Tar get Effects  .......................................................................................5 3  
8. 1. 3  Carci n o ge nicit y  ..........................................................................................................5 4  
8. 2  
P R E D NI S O N E (O R E Q UI V A L E N T C O R TI C O S T E R OI D ) ........................................................ 5 4  
9  
S T U D Y A S S E S S M E N T S  .................................................................................................... 5 6  
9. 1  
M E DI C A L H I S T O R Y ....................................................................................................... 5 6  
9. 2  
D E M O G R A P HI C S  ............................................................................................................ 5 6  
9. 3  
C O N C O MI T A N T M E DI C A TI O N S  ...................................................................................... 5 6  
9. 4  
P H Y SI C A L E X A MI N A TI O N  .............................................................................................. 5 6  
9. 5  
V I T A L S I G N S ................................................................................................................. 5 6  
9. 6  
JOI N T R A N G E O F M O TI O N  ............................................................................................. 5 6  
9. 7  
N E U R O L O GI C A L C R A NI A L N E R V E E X A M A N D M U S C L E S T R E N G T H T E S TI N G O F U P P E R 
E X T R E MI TI E S  ................................................................................................................ 5 6  
9. 8  
E L E C T R O C A R DI O G R A M  ................................................................................................. 5 6  
9. 9  
E C H O C A R DI O G R A M  ....................................................................................................... 5 6  
9. 1 0  C H E S T X -R A Y  ............................................................................................................... 5 7  
9. 1 1  P R E G N A N C Y T E S TI N G A N D C O N T R A C E P TI O N R E Q UI R E M E N T S  ...................................... 5 7  
9. 1 2  C LI NI C A L L A B O R A T O R Y T E S T S  ..................................................................................... 5 8  
9. 1 3  L I V E R P A N E L  ................................................................................................................ 5 8  
9. 1 4  M P S  I G E N E S E Q U E N CI N G  ............................................................................................ 5 8  
9. 1 5  S I N G L E-N U C L E O TI D E P O L Y M O R P HI S M A N A L Y SI S  ......................................................... 5 9  
9. 1 6  V I R A L L O A D  ................................................................................................................. 5 9  
9. 1 7  N E U T R A LI ZI N G A N TI B O DI E S T O A A V 2/ 6  ...................................................................... 5 9  
9. 1 8  C HI M E RI S M A S S A Y  ....................................................................................................... 5 9  
9. 1 9  G A G  T E S TI N G I N U RI N E A N D B L O O D  ........................................................................... 5 9  
9. 2 0  C I R C U L A TI N G A F P  L E V E L  ............................................................................................ 5 9  
9. 2 1  V E C T O R G E N O M E P C R  ................................................................................................. 6 0  
9. 2 2  P U L M O N A R Y F U N C TI O N T E S T S  ..................................................................................... 6 0  
9. 2 3  6 -M I N U T E W
A L K T E S T  ................................................................................................. 6 0  
9. 2 4  V I S U A L A C UI T Y T E S T A N D C O R N E A L C L O U DI N G E X A M  ............................................... 6 0  
9. 2 5  N E U R O C O G NI TI V E A BI LI TI E S T E S T S  .............................................................................. 6 0  
9. 2 6  M RI  O F L I V E R ............................................................................................................... 6 0  
9. 2 7  M RI  O F B R AI N A N D C E R VI C A L S PI N E  ........................................................................... 6 1  
9. 2 8  A D R E N O C O R TI C O T R O PI C H O R M O N E S TI M U L A TI O N ( CO S Y N T R O PI N ) T E S T  ................... 6 1  
9. 2 9  I D U A T E S TI N G I N B L O O D  ............................................................................................. 6 1  
9. 3 0  L I V E R B I O P S Y ............................................................................................................... 6 1  
9. 3 1  L U M B A R P U N C T U R E  ...................................................................................................... 6 1  

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 7  of 8 6  
9. 3 2  IM M U N O G E NI CI T Y A S S A Y S  ........................................................................................... 6 1  
9. 3 3  L A B O R A T O R Y A S S E S S M E N T S I N P E DI A T RI C S U BJ E C T S  .................................................. 6 1  
9. 3 4  E R T  A D MI NI S T R A TI O N L O G .......................................................................................... 6 2  
9. 3 5  E R T  C LI NI C A L A S S E S S M E N T  ........................................................................................ 6 2  
1 0  S A F E T Y M O NI T O RI N G A N D A D V E R S E E V E N T S  .................................................... 6 3  
1 0. 1  D E FI NI TI O N S  ................................................................................................................. 6 3  
1 0. 1. 1  A d verse E v e nt  ............................................................................................................6 3  
1 0. 1. 2  A d verse Reacti o n  .......................................................................................................6 3  
1 0. 1. 3  U ne x pect e d A d verse E ve nt or A d verse Reacti o n  ......................................................6 3  
1 0. 1. 4  Seri o us A d verse E v e nt or Seri o us A d verse Reacti o n  ................................................6 3  
1 0. 1. 5  S us pecte d U ne x p ecte d S eri o us A d verse Reacti o n  .....................................................6 4  
1 0. 2  A D V E R S E E V E N T R E P O R TI N G P E RI O D  ........................................................................... 6 4  
1 0. 3  R E C O R DI N G O F A N A D V E R S E E V E N T  ............................................................................. 6 4  
1 0. 4  S E RI O U S A D V E R S E E V E N T R E P O R TI N G P E RI O D  ............................................................. 6 5  
1 0. 5  R E C O R DI N G O F A S E RI O U S A D V E R S E E V E N T  ................................................................. 6 5  
1 0. 6  S U S A R  R E P O R TI N G O B LI G A TI O N S  ............................................................................... 6 6  
1 0. 7  P R E G N A N C Y A N D P R E G N A N C Y O F A P A R T N E R R E P O R TI N G  ........................................... 6 6  
1 1.  T R E A T M E N T S C H E D U L E, D O S E E S C A L A TI O N, A N D S T O P PI N G R U L E S  ........ 6 7  
1 1. 1  S C H E D U L E F O R S U BJ E C T T R E A T M E N T  ........................................................................... 6 7  
1 1. 2  D O S E E S C A L A TI O N R U L E S  ............................................................................................ 6 7  
1 1. 3  P E DI A T RI C D O SI N G  ....................................................................................................... 6 7  
1 1. 4  E R T  W
I T H D R A W A L ...................................................................................................... 6 8  
1 1. 5  S T U D Y  S T O P PI N G R U L E S  ............................................................................................... 6 8  
1 2  S U B J E C T 
WI T H D R A W A L/ DI S C O N TI N U A TI O N, A N D S A F E T Y 
M O NI T O RI N G 
C O M MI T T E E  ................................................................................................................. 7 0  
1 2. 1  S U BJ E C T W
I T H D R A W A L A N D D I S C O N TI N U A TI O N F R O M S T U D Y  .................................... 7 0  
1 2. 2   S A F E T Y M O NI T O RI N G A N D M I TI G A TI O N P L A N  .............................................................. 7 0  
1 2. 3  S A F E T Y M O NI T O RI N G C O M MI T T E E  ............................................................................... 7 1  
1 3  S T A TI S TI C A L A N A L Y SI S A N D D A T A A N A L Y SI S  .................................................... 7 2  
1 3. 1  D E T E R MI N A TI O N O F S A M P L E S I Z E ................................................................................ 7 2  
1 3. 2  S T A TI S TI C A L A N A L Y S E S  ............................................................................................... 7 2  
1 3. 3  A N A L Y SI S O F T H E C O N D U C T O F T H E S T U D Y  ................................................................. 7 2  
1 3. 4  P RI M A R Y E N D P OI N T  ...................................................................................................... 7 2  
1 3. 5  S E C O N D A R Y E N D P OI N T S  ............................................................................................... 7 3  
1 3. 6  E X P L O R A T O R Y E N D P OI N T S  ........................................................................................... 7 3  
1 4  I N V E S TI G A T O R O B LI G A TI O N S ................................................................................... 7 4  
1 4. 1  IN F O R M E D C O N S E N T  ..................................................................................................... 7 4  
1 4. 2  IN S TI T U TI O N A L R E VI E W B O A R D / ET HI C S C O M MI T T E E A N D B I OS A F E T Y C O M MI T T E E  ... 7 4  
1 4. 3  P R O T O C O L A M E N D M E N T S  ............................................................................................. 7 4  
1 4. 4  S U BJ E C T P RI V A C Y  ......................................................................................................... 7 4  
1 4. 5  R E P O R TI N G O B LI G A TI O N S  ............................................................................................. 7 5  
1 5  A D MI NI S T R A TI V E C O N SI D E R A TI O N S  ...................................................................... 7 6  

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 8  of 8 6  
1 5. 1  S T U D Y D O C U M E N T A TI O N .............................................................................................. 7 6  
1 5. 2  R E C O R D R E T E N TI O N  ..................................................................................................... 7 6  
1 5. 3  C A S E R E P O R T F O R M S  .................................................................................................... 7 6  
1 5. 4  T E R MI N A TI O N O F T H E S T U D Y  ........................................................................................ 7 7  
1 5. 5  S T U D Y M O NI T O RI N G  ..................................................................................................... 7 7  
1 5. 6  C O N FI D E N TI A L IN F O R M A TI O N A N D P U B LI C A TI O N  ......................................................... 7 7  
1 5. 7  S T U D Y F U N DI N G  ........................................................................................................... 7 8  
1 6  R E F E R E N C E S  .................................................................................................................... 7 9  
A P P E N DI X 1: S C H E D U L E O F E V E N T S  ............................................................................... 8 1  
A P P E N DI X 2: E R T WI T H D R A W A L S C H E D U L E O F E V E N T S  ....................................... 8 4  
A P P E N DI X 3: I M M U N O S U P P R E S SI O N R E GI M E N .......................................................... 8 5  
A P P E N DI X 4: I N S T R U C TI O N F O R LI V E R BI O P S Y S A M P L E C O L L E C TI O N A N D 
TI S S U E P R E P A R A TI O N  .............................................................................................. 8 6  
 
 
 

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L I S T O F FI G U R E S 
 
F I G U R E 1.   
Z F N -IN D U C E D D S B S S TI M U L A T E T A R G E T E D IN T E G R A TI O N O F A N A A V  D O N O R V I A 
N H EJ  O R H D R.  ......................................................................................................2 4  
F I G U R E 2.   
Z F N -D RI V E N T A R G E TI N G O F H I D U A T O M O U S E A L B U MI N IN T R O N 1  R E S U L T S I N 
S U P R A P H Y SI O L O GI C A L I D U A A C TI VI T Y I N T H E L I V E R, P L A S M A , A N D S P L E E N O F 
W
I L D-T Y P E M I C E. .................................................................................................. 2 6  
F I G U R E 3.   
Z F N -D RI V E N T A R G E TI N G O F H I D U A T O M O U S E A L B U MI N IN T R O N 1  R E S U L T S I N 
H I G H L E V E L S O F I D U A A C TI VI T Y I N T H E L I V E R, P L A S M A , A N D T I S S U E S O F M P S  I 
M I C E. ..................................................................................................................... 2 7  
F I G U R E 4.   
Z F N -D RI V E N H I D U A E X P R E S SI O N R E S U L T S I N R E D U C TI O N O F G A G  I N U RI N E A N D 
T I S S U E S.................................................................................................................. 2 8  
F I G U R E 5.   
S C H E M A O F S T U D Y V I SI T S. .................................................................................... 3 3  
F I G U R E 6.   
S C H E M A O F S B -3 1 8 -1 5 0 2  C O H O R T E N R O L L M E N T . ................................................ 3 5  
 
 
 
 
 

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LI S T O F T A B L E S  
 
T A B L E 1.   
C LI NI C A L L A B O R A T O R Y T E S T S . ............................................................................. 5 8  
 
 
 

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S B -3 1 8 -1 5 0 2 St u d y Pr ot oc ol S y n o psis  
A P h ase 1/ 2 , M ultice nter, O pe n-L a bel, Si n gle -D ose, D ose -R a n gi n g St u d y t o Assess t he S afet y 
a n d 
T oler a bilit y 
of 
S B -3 1 8, 
a r A A V 2/ 6 -b ase d 
Ge ne 
Tr a nsfer  i n 
S u bjects 
wit h 
M uc o p ol ys acc h ari d osis I  ( M P S I) 
S p o ns or  
Sa n ga m o  T hera p e utics , I nc. 
I n vesti g ati o n al 
Pr o d ucts  
S B -3 1 8 is a c o m bi nati o n of 3  rec o m bi na nt a de n o-ass ociate d vir us ser ot y pe 2/ 6 
(r A A V 2/ 6) v ect ors t hat e nc o de: 
•  Z F N 1 ( S B -4 7 1 7 1): L eft -si de zi nc fi n g er n ucl eas e  ( Z F N) t hat tar gets bas e 
pairs 4 4 7 -4 6 1 of t he al b u mi n l oc us relati ve t o t he tra nscri pti o n i nitiati o n site 
(la bele d as S B-A 6 P -Z L E F T ). 
•  Z F N 2 ( S B -4 7 8 9 8): Ri g ht -si de Z F N t hat tar gets base pairs 4 6 8-4 8 5 of t he 
al b u mi n l oc us rel ati ve t o t he  tra nscri pti o n i nitiati o n site (la bele d as S B -A 6 P -
Z RI G H T ). 
•  hI D U A 
D o n or ( S B -I D U A): 
D N A re pair t e m plate t hat e nc o des a 
pr o m ot orless h u ma n i d ur o ni dase ( hI D U A) tr a ns ge ne (l a bele d as S B-A 6 P -
H R L ). 
St u d y Sites  
A p pr o xi matel y 1 2 t o 1 5  sites w orl d wi de. 
St u d y Desi g n  
M ultice nter, o pe n -l a bel, si n gle-d ose, d ose -ra n gi n g st u d y wit h se q ue ntiall y 
e nr olle d a ge c o h orts: a ge > 1 8 (a d u lt c o h orts 1 t hr o u g h 3 ), a ge 1 2 t o 1 7 ( pe diat ric 
c o h orts 4  a n d 5 ), a n d a ge 5 t o 1 1 ( pe diatric c o h orts 6  a n d 7 ). 
St u d y 
R ati o n ale  
M uc o p ol ysacc h ari d osis t y pe I ( M P S I) is a l ys os o mal st ora ge disease ca us e d b y 
deficie nc y of α -L -i d ur o ni dase (I D U A). I D U A is a n e nz y m e t hat is re q uire d f or 
t he de gra dati o n of t he gl yc osa mi n o gl yca ns ( G A Gs) der mat a n s ulfat e ( D S) a n d 
he para n s ulf ate  ( H S). D eficie nc y of I D U A  is t he res ult of m utati o ns i n t he ge ne 
e nc o di n g I D U A. T h e deficie nc y res ults i n a n i na bilit y b y affecte d i n di vi d uals t o 
de gra de G A Gs , w hic h i n t ur n lea ds t o t he acc u m ulati o n of G A Gs wit hi n 
l ys os o mes t hr o u g h o ut t he b o d y, a n d c o ns e q ue nt m ulti -or ga n d ysf u ncti o n a n d 
da ma ge. T he cli nical se v erit y of M P S I de pe n ds o n t he nat ure of t he m utati o nal 
c ha n ges a n d t he de gree of resi d ual I D U A e n z y me acti vit y. Affecte d i n di vi d uals 
ma y de vel o p me ntal ret ar dati o n; ot her ce ntral n er v o us s yste m ma nifestati o ns 
(e. g., h y dr oce p hal us, cer vical c or d c o m pressi o n wit h para ple gia/ q u a dri ple gia); 
or ga n o me gal y; c or neal cl o u di n g; j oi nt stiff ness a n d c o ntract ur es; s kel etal 
def or mities (i ncl u di n g a b n or mal s pi nal b o nes); h eari n g l oss ( deaf ness); her nias; 
c hr o nic restricti ve a n d o bstr ucti ve p ul m o nar y disease; a n d car diac disease 
(i ncl u di n g arr h yt h mias, val ve disease, c or o nar y arter y narr o wi n g, a n d, rarel y, 
car di o m y o pat h y a n d car diac fail ure ). 
C urre nt t hera pies f or M P S I i ncl u de he mat o p oietic ste m cell tra ns pla ntati o n 
( H S C T) a n d e nz y me re pl ace me nt t hera p y ( E R T). H S C T ca n pre ve nt or re verse 
m ost cli nical feat ures, a n d is rec o m me n de d f or patie nts  wit h t he se v ere f or m of 
t he disease ( H urler s y n dr o me [ M P S I H]). H o we v er, t he re p orte d m ort alit y rate 
after H S C T is 1 5 %, a n d t he s ur vi val rate wit h s uccessf ul e n graft me nt is 5 6 %. 

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Patie nts wit h t he atte n uate d f or ms of t he disease ( H urler -Sc h eie s y n dr o me [ M P S 
I H S], Sc heie s y n dr o me [ M P S I S]) are tr eate d wit h E R T usi n g lar o ni dase 
(rec o m bi na nt h u ma n α -L -i d ur o ni dase; Al d uraz y me). Lar o ni das e has bee n s h o w n 
t o i m pr o ve p ul m o nar y f u ncti o n, he pat os ple n o me gal y, a n d e xercise ca p acit y. 
H o we ver, li mitati o ns of E R T i ncl u de  t he nee d f or life-l o n g treat me nt; 
de vel o p me nt of ne utralizi n g a nti b o dies; i na bilit y t o cr oss t he bl o o d brai n b arrier  
( wit h c o nse q ue nt lac k 
of efficac y i n t he 
brai n); c o nti n ue d car diac, 
m usc ul os keletal , a n d o c ular c o m plicati o ns; a n d t he i nc o n ve nie nce of wee kl y 
i ntra ve n o us (I V) i nf usi o ns. 
T he prese nt  st u d y uses Z F N ge ne-s pecifi c tar gete d i nserti o n of a hI D U A 
tra ns ge ne i nt o t he li ver al b u mi n ge n o me l oc us i n s u bjects wit h M P S  I t o pr o vi de 
life-l o n g pr o d ucti o n of hI D U A.  
O bjecti ves  
Pri m ar y O bjecti ve:   
T o e val ua te t he s afet y a n d t olera bilit y of S B-3 1 8 . 
Sec o n d ar y O bjecti ves:  
•  T o e val uat e c h a n ge fr o m 
Baseli ne o ver ti me i n t he f oll o wi n g 
assess me nts :  
o  I D U A acti vit y i n bl o o d. 
o  G A G testi n g i n uri ne. 
o  Fre q u e nc y of E R T a d mi nistrati o n.  
•  T o e val uate A A V 2/ 6 cleara nce . 
 
E x pl or at or y O bjecti ves : 
T o e val uate c ha n ge fr o m Baseli ne o ver ti me i n t he f oll o wi n g assess me nts :  
•  G A G testi n g i n tiss ues (i ncl u di n g bl o o d, li ver tiss ue, a n d cere br os pi nal 
fl ui d [ C S F]). 
•  Ge ne m o dificati o n at t he al b u mi n l oc us i n t he li ver.  
•  I ma gi n g, f u ncti o nal, a n d ne ur oc o g niti ve testi n g rel ate d t o M P S I.  
•  I m m u ne res p o nse t o A A V 2/ 6, Z F Ns , a n d I D U A. 
Fr o m c o nse nti n g s u bjects, resi d ual sa m ples ma y b e use d f or f ut ure researc h 
o bjecti ves . 
E n d p oi nts  
Pri m ar y E n d p oi nt:  
 
•  I n ci de nce of treat me nt-e mer ge nt A E s (i ncl u di n g S A Es). 
•  A d diti o nal safet y e val u ati o ns i ncl u de:  
o  R o uti ne he mat ol o g y, c he mistr y a n d li ver f u ncti o n la b orat or y tests, 
vital si g ns, 
p h ysical 
e xa m i nati o n, 
electr ocar di o gra m ( E C G), 
ec h ocar di o gra m ( E C H O), a n d c o nc o mita nt me dicati o n s.  
o  M o nit ori n g of c hi meris m i n p ost -H S C T s u bjects.  
o  Cra nial ner ve e xa m a n d m uscle stre n gt h testi n g.  
o  Serial α -fet o pr otei n (A F P ) testi n g a n d m a g netic res o na nce i ma gi n g 
(M RI ) of li ver t o e v al uat e f or li ver mass.  
 

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Sec o n d ar y E n d p oi nts:  
•  C ha n ge fr o m B aseli ne i n:  
o  I D U A acti vit y meas ure d i n bl o o d. 
o  T otal G A G, D S G A G, a n d H S G A G le vels (e x presse d as rati o t o 
creati ni ne ) meas ure d i n uri ne . 
o  M o nt hl y a n d a n n ualize d fre q ue nc y a n d d ose of Al d uraz y me ( or 
e q ui vale nt E R T) . 
•  A A V 2/ 6 cleara nce meas ure d b y vect or ge n o mes i n plas ma, sali va, uri ne, 
st o ol, a n d se me n b y P C R. 
E x pl or at or y E n d p oi nts:  
•  C ha n ge fr o m Baseli ne i n:  
o  T otal G A G, D S G A G, a n d H S G A G le vels meas ure d i n  tiss ues 
(i ncl u di n g bl o o d, li ver tiss ue, a n d C S F). 
o  Perce nta ge a n d d ura bilit y of ge n e m o dificati o n at t he al b u mi n l oc us 
i n li ver tiss ue o btai ne d at bi o ps y. 
o  F orce d vital ca p acit y meas ure d b y p ul m o nar y f u ncti o n tests ( P F Ts) .  
o  Dista nce wal k e d meas ure d b y si x -mi n ute wal k test ( 6 M W T).  
o  J oi nt ra n ge of m oti o n (J R O M). 
o  M RI of li ver t o e val uate li ver a n d s plee n v ol u me.  
o  M RI of brai n a n d cer vical s pi ne t o e val uat e cli nical s oft tiss ue a n d/ or 
b o ne . 
o  Ne ur oc o g niti ve a bilities b y W A SI -II (Wec hsler A b bre viate d Scale 
of I ntelli ge nce, Sec o n d E diti o n;  S ha pir o et al. 2 0 1 5 ), W P P SI -I V 
(Wec hsl er Presc h o ol a n d Pri mar y Scale of I nt elli ge nce ), or B SI D-III 
(Ba yle y Scales of I nfa nt De vel o p me nt ), a n d b y V A B S-II ( Vi nela n d 
A da pti ve Be ha vi or Scales) . 
o  E ye e xa m f or c or neal cl o u di n g a n d visi o n testi n g.  
o  Hist o pat h ol o gical e xa m of li ver tiss ue.  
o  I m m u ne res p o ns e t o A A V 2/ 6, Z F N s, a n d I D U A meas ure d i n ser u m.  
St u d y 
P o p ul ati o n  
S u bjects wit h M P S I  dise ase , se q u e ntiall y e nr olle d i n a ge c o h orts: a ge > 1 8 (a d ult 
c o h orts 1 t hr o u g h 3), a g e 1 2 t o 1 7 ( pe diatric c o h orts 4  a n d 5 ), a n d a g e 5 t o 1 1 
( pe diatric c o h orts 6  a n d 7 ). 
N u m ber of 
S u bjects  
U p t o 2 7 .  
I ncl usi o n & 
E xcl usi o n 
Criteri a  
I ncl usi o n Criteri a  
1.  Si g ne d  i nf or me d c o nse nt. 
2.  > 5  y ears of a g e: 
a. A d ult c o h orts 1 t hr o u g h 3 : ≥1 8  y ears of a g e; 
b.  Pe diatric c o h orts 4  a n d 5 : 1 2 t o 1 7  years of a ge ; a n d  
c. Pe diatric c o h orts 6  a n d 7 : 5 t o 1 1  years  of a ge . 
3.  Cli nical dia g n osis of 
M P S I ; I D U A defi cie nc y  c onfir m e d b y  ge n e 
se q ue nci n g. 

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4.  Se x uall y mat ure s u bjects m ust a gree t o use a barrier c o ntrace pti ve met h o d 
f or pre ve nti o n of A A V tra nsfer as f oll o ws: f or fe male s u bjects t his mea ns 
t hat t he s u bjects’ part ners m ust use a c o n d o m fr o m d osi n g wit h S B -3 1 8 u ntil 
at least 3 c o nsec uti ve plas ma sa m ples after a d mi nistrati o n of S B -3 1 8  are 
ne gati ve f or A A V 2/ 6; f or male s u bjects t his mea ns t hat t he s u bjects  m ust use 
a c o n d o m a n d m ust refrai n fr o m s per m d o nati o n fr o m t he ti me of S B-3 1 8 
a d mi nistrati o n 
u ntil 
at least 
3  c o ns ec uti ve 
se me n 
s a m ples 
aft er 
a d mi nistrati o n of S B -3 1 8  are ne g ati ve f or A A V 2/ 6. A d diti o nall y, fe male 
partici pa nts of c hil d -beari n g p ote ntia l m ust c o nse nt t o use a hi g hl y effecti ve 
met h o d of c o ntrace pti o n . 
5.  M RI ne g ati ve f or li ver mass as rea d b y a ra di ol o gist . 
E xcl usi o n Criteri a  
1.  K n o w n  t o be u nres p o nsi ve t o E R T. 
2.  Ne utralizi n g  a nti b o di es i n ser u m (i m m u ne res p o nse) t o A A V 2/ 6 .  
3.  Ser i o us i nterc urre nt ill ness or cli nicall y si g nifica nt or ga nic disease ( u nless 
sec o n dar y t o M P S I) s u c h as car di o vas c ular, he p atic, p ul m o nar y, ne ur ol o gic, 
or re nal disease . 
4.  Recei vi n g a nti viral t hera p y f or he p atitis B or C, or wit h acti ve he patitis B 
( HB V  D N A p osit i ve or H B V s urface a nti ge n p ositi ve ) or he p atitis C ( H C V 
R N A viral l oa d)  or h u ma n i m m u n o deficie nc y vir us  (HI V )-1/ 2 ( HI V R N A  
viral l oa d  or HI V a nti b o d y p ositi ve); t o be c o nsi dere d ne gati ve  f or he patitis 
C  after treat me nt of a n acti ve H C V i nfecti o n, viral assa ys i n 2  sa m ples 
c ollecte d at least 6  m o nt hs a part m ust be ne gati ve . 
5.  Lac k of t olera n ce t o E R T  wit h si g nifica nt i nf usi o n-ass ociate d reacti o ns 
(I A Rs) or occ urre nce of a na p h yla xis . 
6.  P ol y m or p his ms i n t he Z F N -tar gete d re gi o n of t h e al b u mi n l oc us. 
7.  Li ver fi br osis sc ore of 3 or 4 o n a 0 t o 4 p oi nt scale  (Des met et al. 1 9 9 4 ) if 
s u bject has ha d a li ver bi o ps y wit hi n 2 years of Scree ni n g . 
8.  Mar kers of he p ati c d ysf u ncti o n as e vi de nce d b y o ne or m ore of t he 
f oll o wi n g: 
a. Platelet c o u nt < 1 0 0 , 0 0 0/ μ L. 
b.  Al b u mi n ≤3. 2  g/ d L . 
c. T otal bilir u bi n > 1. 5 x u p per li mit of n or mal ( U L N ) a n d direct bilir u bi n 
≥0. 5 m g/ d L . 
d.  Al kali ne p h os p hatase > 2. 0 x U L N . 
e. A la ni ne a mi n otra nsferas e (A L T ) or as partate a mi n otra nsferas e  (A S T ) 
> 2. 0 x U L N . 
9.  Creati ni ne ≥ 1. 5 m g/ d L . 
1 0.  Wei g ht < 2 0 k g at Scree ni n g.  
1 1.  P re g na nt or breastfee di n g fe male. 
1 2.  C o ntrai n dicati o n t o t he use of c ortic oster oi ds .  

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1 3.  C ur re nt treat me nt wit h s yste mic (I V or oral) i m m u n o m o d ulat or y a ge nt or 
ster oi d use (t o pical treat me nt all o we d, e. g., f or ast h ma or ecze ma). 
1 4.  Hist or y of acti ve mali g na nc y i n past 5 years ( n o n-mela n o ma s ki n ca ncer or 
cer vical ca n cer i n sit u per mitte d) . 
1 5.  Partici pati o n i n  pri or  i n vesti gati o nal dr u g or me dical de vice st u d y wit hi n t he 
pre vi o us 3  m o nt hs . 
1 6.  Pri or treat m e nt wit h a ge ne t hera p y pr o d uct.  
1 7.  Hist or y of alc o h ol or s u bsta nce a b use  t hat i n t he o pi ni o n of t he Pri nci pal 
I n v esti gat or ma y i nterfere wit h st u d y c o m plia nce. 
1 8.  Hist or y of t hera p e utic n o n -a d here nce. 
1 9.  Ele vate d or a b n or mal circ ulati n g A F P . 
2 0.  A n y ot her reas o n t hat, i n t he o pi ni o n of t he Pri n ci p al I n vesti gat or or M e dical 
M o nit or, w o ul d re n der t h e s u bject u ns uita ble f or partici pati o n i n t he st u d y . 
D ose &  
R ati o n ale f or 
D ose 
Selecti o n  
T he d oses t o be e val u ate d were sel ecte d base d o n  res ults of st u dies i n n o n -h u ma n 
pri mates, a n d  e mer gi n g h u ma n safet y data fr o m t he h u ma n st u d y S B-9 1 3 -1 6 0 2 
i n w hic h t he st u d y treat me nt was c o m p ose d of t he sa me Z F N c o m p o ne nts 
deli vere d b y a n A A V 2/ 6 vect or i n s u bjects wit h 
M P S II diseas e.  C urre nt 
n o ncli nical data s u p p ort t he use of a Z F N 1: Z F N 2: hI D U A D o n or rati o of 1: 1: 8 . 
T he c o nfi g urati o ns of Z F Ns a n d h I D U A D o n or  r A A V 2/ 6 vect ors f or t he d oses 
are ill ustrate d i n t he ta ble bel o w. 
C o h ort  
Z F N 1 ( S B -
4 7 1 7 1)  
( v g/ k g) 
Z F N 2 ( S B -4 7 8 9 8)  
( v g/ k g) 
hI D U A  D o n or ( S B -
I DU A ) 
( v g/ k g) 
T otal r A A V 
( v g/ k g) 
1  
1. 0 0 E + 1 2  
1. 0 0 E + 1 2  
8. 0 0 E + 1 2  
1. 0 0 E + 1 3  
2  
5. 0 0 E + 1 2  
5. 0 0 E + 1 2  
4. 0 0 E + 1 3  
5. 0 0 E + 1 3  
3  
1. 2 0 E + 1 3  
1. 2 0 E + 1 3  
9. 6 0 E + 1 3  
1. 2 0 E + 1 4  
4  
T B D  
T B D  
T B D  
T B D  
5  
T B D  
T B D  
T B D  
T B D  
6  
T B D  
T B D  
T B D  
T B D  
7  
T B D  
T B D  
T B D  
T B D  
 
 
Tre at me nt 
Pl a n & 
Sc he d ule  
S u bjects w h o satisf y al l eli gi bilit y criteria will be e nr olle d i nt o o ne of t he 
f oll o wi n g treat me nt c o h orts as descri be d bel o w : 
C o h ort #  
A ge 
R a n ge 
( y) 
T ot al D ose ( v g/ k g)  
# S u bjects  
1  
≥1 8  
1. 0 0 E + 1 3  
1  
2  
≥1 8  
5. 0 0 E + 1 3  
2  
3  
≥1 8  
1. 2 0 E + 1 4  
2  
4  
1 2 -1 7  
T B D  
2  
5  
1 2 -1 7  
T B D  
2  
6  
5 -1 1  
T B D  
2  
7  
5 -1 1  
T B D  
2  
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 1 6  of 8 6  
F or eac h d ose c o h ort after C o h ort 1, t w o s u bjects will be d ose d ≥ 4 wee ks a part . 
Re vie w b y a n i n de pe n de nt, e xter nal S afet y M o nit ori n g C o m mittee ( S M C) will 
occ ur after all s u bjects i n eac h c o h ort ha ve ≥ 4 wee ks of safet y data .  
T he pe diatri c c o h orts will be e nr olle d o nl y after re vie w of c u m ulati ve a d ult 
safet y data b y t he S M C  (see Secti o n 1 1 . 3). T he st arti n g d ose f or pe diatric c o h orts 
4  t hr o u g h 7  will be deci de d base d o n S M C re vie w of st u d y data, a n d m ust meet 
pre -defi ne d safet y criteria (see P e di atric D osi n g ).   
A p pr o xi matel y 2 a d diti o nal s u bjects ma y be a d de d t o a n y c o h ort after S M C 
re vie w of st u d y d ata if safet y criteria are 
met (see Safet y 
M o nit ori n g 
C o m mittee), wit h u p t o a t otal of 2 7  s u bjects i n t he st u d y. 
S u bjects w h o rece i ve d E R T  pri or t o st u d y e nr oll me nt will c o nti n ue t o recei ve 
E R T d uri n g t he st u d y a n d re mai n o n t heir c urre nt sc he d ule per sta n d ar d of care , 
u nless t he y u n der g o  pr ot oc ol -s pecifie d E R T wit h dra wal (see E R T Wit h dr a w al  
a n d Secti o n 1 1. 4 ). H o we ver, E R T will be o mitte d d uri n g t he wee k  of t he S B -3 1 8 
i nf usi o n t o facilitate acc urate b aseli ne testi n g  (e. g., of G A G le vels  i n uri ne, a n d 
of I D U A acti vit y  i n bl o o d) t o all o w a wee k free of E R T after t he S B-3 1 8 
i nf usi o n. 
T o mi ni mize t he p ote ntial i m m u ne res p o nse t o t he A A V  ca psi d pr otei n, t he 
e n gi neere d Z F Ns, or t he e n d o ge n o us hI D U A, a n d t o pres er ve he p atic f u ncti o n, 
pre d nis o ne or e q ui vale nt c ortic oster oi d will be a d mi nistere d pr o p h ylacticall y 
starti n g 2 da ys pri or t o S B-3 1 8 i nf usi o n , a n d will be ta pere d o ver a p eri o d of 
a ppr o xi matel y 2 0 wee ks (see A p pe n di x 3 ). 
T he t hree c o m p o ne nts of S B -3 1 8 ( Z F N 1, Z F N 2, a n d hI D U A D o n or) will eac h 
be a d de d t o 2 0 0 m L of dil ue nt (refer t o t he P har mac y Ma n ual) a n d a dj uste d t o 
0. 2 5 % h u ma n ser u m al b u mi n. T otal i nf usi o n v ol u mes will de pe n d o n a s u bject’s 
c o h ort assi g n me nt a n d b o d y wei g ht ( k g). I V i nf usi o ns will be a d mi nistere d w hile 
s u bjects are i n t he h os pit al or ac ute care facilit y  (refer t o t he P har mac y Ma n ual).  
S u bject s will re mai n i n t he h os pital or ac ute care facilit y  f or at least 2 4 h o urs  
after c o m pleti o n of S B -3 1 8 i nf usi o n f or o bser vati o n, a n d will be disc har ge d 
w he n all A Es a n d vital si g ns ( te m perat ur e, heart rate , res pirat or y rate, a n d bl o o d 
press ure ) are sta ble. 
After b ei n g disc har ge d fr o m t he h os pital or ac ute care facilit y , st u d y visits are 
sc he d ule d o n Da y 7; Wee ks 2, 4, 6, 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, 4 8, a n d 
5 2; a n d M o nt hs 1 5, 1 8, 2 1, 2 4, 2 7, 3 0, 3 3, a n d 3 6 .  
Li ver f u ncti o n tests ( A S T , A L T , t otal a n d direct bilir u bi n, al kali ne p h os p hatase, 
lactate de h y dr o ge n ase ( L D H), al bu mi n, a n d t otal pr otei n le vels) 
will be 
c o n d ucte d f or e v al uati o n of A A V -me diate d i m m u n o ge nicit y t wice a wee k 
d uri n g t he first 2 0 wee ks after S B -3 1 8  i nf usi o n, an d ma y be c o n d u cte d  re m otel y. 
B l o o d sa m ples f or li ver f u ncti o n tests will be dra w n 2-4  da ys a p art w he n 
p ossi ble, e xce pt f or t he first wee k w he n t he y  will be dra w n o n t he Da y 1 a n d 
Da y 7 visits . Li ver f u ncti o n tests will s u bse q ue ntl y be c o n d ucte d at all st u d y  
visits .  
If i n s pite of pretreat me nt wit h pre d nis o ne or e q ui vale nt c ortic oster oi d t here i s 
e vi de nce of tr a nsa mi nitis, t he d ose of pre d nis o n e  or e q ui v ale nt c ortic oster oi d 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 1 7  of 8 6  
will be i ncrease d o n a case -b y -case basis, a n d l i ver f u ncti o n will be ass esse d 
t wice a w ee k  u ntil n or malizati o n of li ver e nz y mes , a n d t he n p er pr ot oc ol  
t hereafter.  
D ose 
Esc al ati o n  
Wit hi n eac h c o h ort, tr eat me nt will be sta g gere d s o t hat eac h s u bse q ue nt s u bject 
will n ot  be i nf use d u ntil t he prece di n g s u bject has bee n o bser ve d f or at least 
4  wee ks  f oll o wi n g a d mi nistrati o n of S B-3 1 8 .  
D ose escalati o n t o t he ne xt c o h ort will n ot occ ur u ntil at least 4  wee ks after t he 
last s u bject i n t he prece di n g c o h ort has bee n d os e d , t he safet y data fr o m t he pri or 
c o h ort has bee n re vie we d b y t he S M C , a n d t he S M C has a gree d t o d ose escalate .  
D osi n g a n d d ose es calati o n will be pa use d if a Gra d e 3 or hi g h er a d v erse e ve nt 
(A E ) o cc urs,  or  if t w o Gra de 2 A Es occ ur wit hi n t h e sa me or ga n class a n d p ersist 
f or m ore t ha n 2  wee ks wit h t hera p y, pr o vi de d t hese A Es are n ot relate d t o t he 
pri mar y M P S I dise ase or treat me nt of t h e M P S I disease. I n s u c h a n e v e nt, t he 
S M C will be c o n ve n e d t o assess f or p ote ntial d os e li miti n g t o xicit y ( D L T) , a n d 
t o pr o vi de rec o m me n dati o ns o n w het her t o e x pa n d t he c o h ort at t he sa me d ose 
le vel, t o d ose de -escalat e, or t o c o nti n ue t he st u d y as pla n ne d (refer t o t he 
St o p pi n g R ule s). 
Pe di atric 
D osi n g  
Pe diatric d osi n g will n ot be i nitiate d u ntil a d ult safet y data has bee n o btai n e d a n d 
re vie we d b y t h e S M C, a n d o nl y after t he f oll o wi n g c o n diti o ns ha ve bee n met: 
•  ≥6 m o nt hs of safet y data fr o m 2 a d ults treate d wit h S B -3 1 8  at a n y d ose; a n d  
•  ≥4 wee ks of safet y data fr o m 2 a d ults treate d wit h S B -3 1 8  at t he i nte n de d 
pe diatric d ose.  
Y o u n ger pe diatric s u bjects ( C o h orts 6  a n d 7 ) will  n ot be d ose d u ntil ol der 
pe diatric s u bjects ( C o h orts 4  a n d 5 ) ha v e bee n d os e d at t he sa me d ose le vel, a n d 
≥4 wee ks of s afet y d ata fr o m eac h ol der s u bject h as bee n re vie we d b y t he S M C.  
E R T 
Wit h dr a w al  
S u bjects  w h o recei ve d S B -3 1 8  ma y n o l o n ger re q uire wee kl y a d mi nistrati o n of 
E R T, a n d t heref ore ma y be c o nsi dere d f or wit h dr a wal of E R T (if a p plica bl e).  
E R T wit h dra wal will be a c o ntr olle d pr ocess , wit h a d diti o nal safet y m o nit ori n g 
t o re d uce p ote ntial ris k t o t he s u bject, a n d is a n o pti o nal part of t he st u d y . 
E R T wit h dra wal ma y be i nitiate d b y t he Pri nci pal I n v esti gat or after c o ns ultati o n 
wit h t he S p o ns or, a n d o nl y i n s u bjects w h o  are willi n g a n d w h o meet all of t he 
f oll o wi n g criteria: 
•  are ≥1 2 w ee ks p ost-a d mi nistrati o n of S B -3 1 8 ; 
•  are me dicall y sta ble a n d ca n t olerate te m p orar y disc o nti n uati o n of E R T at 
t he j u d ge me nt of t he Pri n ci pal I n vesti gat or; a n d 
•  agree t o a d diti o nal safet y m o nit ori n g a n d cli nical la borat or y  testi n g u ntil t he 
E R T W it h dra wal F oll o w -U p visit (see A p pe n di x 2 ). 
E R T d oes n ot nee d t o be restarte d after t he E R T Wit h dra wal F oll o w -U p visit. 
H o we ver, E R T ma y be re -i nitiate d at a n y ti me base d o n cli nical cir c u msta nces 
or at t he j u d ge me nt of t h e Pri nci pal I n vesti gat or. 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 1 8  of 8 6  
St u d y 
D ur ati o n  
T he d urati o n of st u d y partici pati o n will be a p pr o xi matel y 3 9  m o nt hs f or eac h 
s u bject, di vi de d i nt o a p pr o xi matel y 3 
m o nt hs f or Scree ni n g f oll o we d b y 
3 6  m o nt hs f or treat me nt a n d st u d y f oll o w -u p.  
U p o n c o m pleti o n of t h e st u d y, s u bjects will be as k e d t o partici pate i n a se p arate 
L o n g -ter m F oll o w-U p ( L T F U) St u d y t o m o nit or t he l o n g -ter m safet y of S B -3 1 8 . 
T o alle viate st u d y b ur de n, st u d y s u bjects ma y parti ci pate i n t he L T F U  St u d y after 
at least 1 2 m o nt hs of f oll o w -u p i n t his st u d y. St u d y partici pa nts w h o wis h t o 
e nr oll i n t he L T F U  St u d y wit h less t ha n 1 2 m o nt hs of f oll o w-u p i n t his pri mar y 
st u d y ma y be c o nsi dere d o n a cas e -b y -case basis at t he j u d ge me nt of t he 
Pri nci pal I n v esti gat or a n d after c o ns ultati o n wit h t he S p o ns or.  
S afet y  
M o nit ori n g 
C o m mittee  
A n e xter nal  S M C  wit h a p pr o priate me dical a n d s cie ntific e x pertise will pr o vi de 
a d vice t o Sa n g a m o re gar di n g s u bject safet y t hr o u g h o ut t he st u d y. T he S M C will 
be c o n ve ne d  after t he c o m pleti o n of eac h c o h ort t o deter mi ne if it is safe t o 
pr ocee d wit h t he ne xt d ose c o h ort , a n d t o pr o vi de rec o m me n dati on o n pe diatric 
d osi n g  a n d e x pa nsi o n of a n y c o h ort . T he S M C ma y als o be c o n ve ne d at a n y ti me 
if t here are e xcessi ve or u ne x pecte d t o xicities ass o ciate d wit h t h e c o n d uct of t he 
pr ot oc ol. S pecificall y, t h e S M C will be c o n ve ne d if t he f oll o wi n g occ urs:  
•  A n y o ne Gra de 3 or hi g h er  A E, or a n y t w o Gra de 2 A E s i n t he sa me s yste m 
or ga n class t hat persist f or  m ore t ha n 2 wee ks wit h t hera p y, pr o vi de d  t h ese 
A Es are n ot r elate d t o t he pri mar y M P S I dise ase or treat me nt of t he M P S I 
disease . 
•  S A E n ot relate d t o t he pri mar y M P S I diseas e. 
•  Deat h of a s u bj ect . 
•  De vel o p me nt of a m ali g na nc y . 
T he S M C will t he n e val uate all data t o deter mi ne if c ha n ges s h o ul d be ma de  t o 
t he st u d y or if accr ual s h o ul d be halte d.  
T he S M C ma y als o rec o m me n d c ha n g es t o t he e nr oll me nt of c o h o rts bas e d o n 
c u m ulati ve a d ult a n d pe diatric safet y a n d efficac y data fr o m t his a n d si milar 
o n g oi n g first -i n-h u ma n cli nical trials t hat are s p o ns ore d b y Sa n ga m o a n d t hat use  
i n viv o r A A V 2/ 6-base d g e ne tra nsfer of Z F Ns . S p ecificall y, st u d y S B-9 1 3 -1 6 0 2 
i n M P S II s u bjects us es  i de ntical Z F Ns c o m p o ne nts ( S B -4 7 1 7 1 a n d S B -4 7 8 9 8) 
as t he prese nt st u d y i n c o m bi nati o n wit h a differe nt d o n or c D N A (e n c o di n g 
h u ma n i d ur o nate -2 -s ulf atase) ( Cli nicaltrials. g o v 
N C T 0 3 0 4 1 3 2 4). Gi ve n t he 
si milarities of t he a p pr oac hes, rele va nt data fr o m st u d y S B -9 1 3 -1 6 0 2 a n d ot her 
trials s p o ns ore d b y Sa n ga m o ma y be s hare d wit h t he S M C t o e x pa n d t he cli nical 
e x perie n ce, p artic ularl y as it relates t o safet y a n d d ose , a n d s u c h d ata ca n b e use d 
b y t he S M C t o i nf or m its rec o m me n dati o ns f or t he prese nt st u d y . 
W he n n o f urt h er e nr olli n g or d osi n g decisi o ns are re q uire d of t he S M C, t he S M C 
will n o l o n ger meet.  Sa n ga m o will c o nti n ue t o re vie w s u bject safet y d ata o n a n 
o n g oi n g basis . 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 1 9  of 8 6  
S afet y 
M o nit ori n g  &  
Miti g ati o n  Pl a n  
T he li ver f u ncti o n ( t otal a n d direct bilir u bi n, al kali ne p h os p hatase, A L T, A S T, 
L D H, al b u mi n, a n d t otal pr otei n) of s u bjects 
will be 
m o nit ore d cl osel y 
t hr o u g h o ut t he st u d y.  
Ke y p ote ntial a ntici pate d ris ks are:  
•  De vel o p me nt of tr a nsa mi nitis d ue t o cell -me diat e d i m m u nit y t o t he A A V 
ca psi d pr otei n, t he e n gi neere d Z F Ns, or t he e n d o ge n o us hI D U A ; t o mi ni mize 
t he p ote ntial i m m u ne res p o nse a n d t o preser ve he patic f u ncti o n , pre d nis o n e  
or e q ui vale nt c ortic oster oi d  will be a d mi nistere d pr o p h ylacticall y starti n g 2 
da ys pri or t o S B -3 1 8 i nf usi o n  a n d will be  ta pere d o ver a p pr o xi matel y  2 0 
wee ks (s ee  A p p e n di x 3 ). 
•  Re d ucti o n i n al b u mi n s y nt hesis; t his is n ot e x pecte d gi ve n t he s mall fracti o n 
( < 1 %) of tra ns d uce d cells i n w hic h t h e al b u mi n l o c us will be disr u pte d , a n d 
has n ot bee n o bser ve d i n a ni mal st u dies i n w hic h le vels of tra ns d ucti o n a n d 
al bu mi n l oc us disr u pti o n e xcee de d b y se veral f ol d t h ose e x pecte d i n h u ma ns . 
•  Off -tar get 
m o dificati o n at t he str uct ur al 
mai nte na nce of c hr o m os o mes 
fle xi ble hi n ge d o mai n c o ntai ni n g 1 (S M C H D 1 ) l oc us; t his is n ot e x pecte d 
gi ve n t hat n o off -tar get acti vit y has bee n o bser ve d at cli nicall y rele va nt le vels 
of al b u mi n o n -tar get acti vit y i n h u ma n cells i n vitr o. 
St o p pi n g 
R ules  
T he S M C will be c o n ve ne d t o assess w het her c h a n ges s h o ul d be ma de t o t he 
st u d y or w het her t he st u d y s h o ul d be st o p pe d if a n y of t he f oll o wi n g criteria are 
met:  
•  C o m pleti o n of a c o h ort . 
•  A n y o ne Gra d e 3 or hi g her  A E , or a n y t w o Gra de 2 A E s i n t he sa me s yste m 
or ga n class t hat persist f or  m ore t ha n 2 wee ks wit h t hera p y, pr o vi de d  t hes e 
A E s are n ot relate d t o t he pri mar y M P S I  disease or treat me nt of t he M P S I 
disease . 
•  S A E n ot relate d t o t he pri mar y M P S I diseas e.  
•  Deat h of a s u bj ect . 
•  De vel o p me nt of a m ali g na nc y . 
T he st u d y ma y als o be st o p pe d f or a n y of t he f oll o wi n g reas o ns: 
•  Sa n ga m o  T hera pe utics , I n c. ( Sa n ga m o), i n c o ns ultati o n wit h t he S M C or 
Re g ulat or y A ge nc y, deci des f or a n y reas o n t hat s u bject safet y ma y be 
c o m pr o mise d b y c o nti n ui n g t he st u d y . 
•  Sa n ga m o deci des t o disc o nti n ue de vel o p me nt of S B -3 1 8 . 
W he n n o f urt h er e nr olli n g or d osi n g decisi o ns are re q uire d of t he S M C, t he S M C 
will n o l o n ger meet.  Sa n ga m o will c o nti n ue t o re vie w s u bject safet y d ata o n a n 
o n g oi n g basis . 
S a m ple Size  
T his st u d y will e nr oll  u p t o a t otal of 2 7  s u bj ects (1 s u bject i n C o h ort 1  a n d 2  
s u bjects i n eac h of t he ot her 6 c o h orts, wit h p ote ntial 
e nr oll me nt of 
a p pr o xi matel y 2  a d diti o nal s u bjects i n a n y c o h ort). T o o btai n  a n e val ua ble 
sa m ple size, s u bjects w h o pre mat urel y disc o nti n ue t he st u d y pri or t o t he 
1 2  m o nt hs of st u d y f oll o w-u p (i.e., s u bjects w h o were e nr olle d b ut n ot d os e d, or 
were l ost t o f oll o w-u p) m a y be re pl ace d at t he discreti o n of Sa n ga m o .  

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 2 0  of 8 6  
St atistic al 
Met h o ds  
T he pri mar y o bjecti ve of t his st u d y is t o e val uate t he safet y a n d t olera bilit y of 
S B -3 1 8 . All statistical s u m maries will be descri pti ve i n nat ure (e. g., m ea ns, 
sta n dar d de viati o ns, a n d perce nt a ges). All s u bjects w h o recei ve a n y p orti o n of 
t he S B-3 1 8  i nf usi o n will be i ncl u de d i n t he a nal ys es, e ve n t h ose w h o wit h dra w 
pre mat urel y fr o m t he st u d y. All res ults will be prese nte d se paratel y f or eac h of 
t he S B-3 1 8 d ose le vels. All a nal yses, s u m maries , a n d listi n g will be perf or me d 
usi n g S A S versi o n 9. 2 or lat er.  
 
Pri m ar y S afet y A n al yses  
Treat me nt -e mer ge nt  A E s will be s u m marize d o verall a n d b y treat me nt c o h ort.  
F or eac h s u bject, t he ma xi m u m re p ort e d se verit y of eac h A E  will be use d i n t he 
s u m maries b y se verit y gra de.  I n a d diti o n, all S A Es  a n d A Es rel ate d t o s t u d y 
treat me nt will be s u m marize d.  
La b orat or y d ata will be s u m marize d f or eac h ti me -p oi nt at  w hic h s peci me ns are 
c ollecte d. C ha n ge -fr o m-Baseli ne v al ues 
ma y be calc ulat e d f or s electe d 
la b orat or y p ara m eters. S hift -ta bles ( C ha n g e-fr o m-Baseli ne rel ati ve t o t he n or mal 
ra n ge) m a y be c o nstr ucte d f or select e d la b orat or y para meters. 
 
Sec o n d ar y A n al yses  
At eac h sa m pli n g ti me p oi nt, t he a ct ual val ue a n d t he c ha n ge fr o m bas eli ne f or 
I D U A acti vit y a n d uri n e G A G le vels will be s u m marize d usi n g d escri pti ve 
statistics a n d pl otte d o ver ti me b y treat me nt c o h ort. 
F or s u bjects w h o u n der g o E R T wit h dra wal, c h a n ges  fr o m pre- t o p ost-E R T 
wit h dra wal  i n t he fre q ue nc y a n d d ose of E R T i nf usi o ns will be e val uate d a n d 
s u m marize d usi n g a n n ualize d t otal d ose a n d n u m ber of i nf usi o ns. D urati o n of 
E R T wit h dra wal ma y als o be a nal yze d.  
A A V 2/ 6 cleara nce meas ure d b y vect or ge n o mes i n t he differe nt sa m ples will be 
pl ot te d o ver ti me b y treat me nt c o h ort. 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 2 1  of 8 6  
A B B R E VI A TI O N S  
A A V   
a de n o -ass o ciate d vir us  
A A V 2/ 6  
a de n o -ass o ciate d vir us ser ot y pe 2/ 6  
A C T H   
a dre n oc ortic otr o pic h or m o n e 
A E  
 
a d verse e ve nt/e x p erie nce  
A F P  
 
α -fet o pr ot ei n 
A L T   
ala ni ne a mi n otra nsf eras e ( S G P T)  
A N O V A  
a nal ysis -of -varia nce   
 
A R  
 
a d verse reacti o n   
A S T  
 
as partate a mi n otra nsferas e ( S G O T)   
B S C  
 
Bi o Safet y C o m mittee  
B SI D -III 
Ba yle y Scales of I nfa nt De vel o p me nt  
C N S   
ce ntral ner v o us s yste m  
C R F  
 
case re p ort f or m  
C S F  
 
cere br os pi nal fl ui d  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts   
D L T   
d ose -li miti n g t o xicit y  
D N A   
de o x y ri b o n ucleic aci d 
D S  
 
der mata n s ulfat e  
D S B   
d o u ble stra n d brea k  
E C G   
electr ocar di o gra m  
E C H O   
ec h ocar di o gra m  
e C R F  
electr o nic C R F  
E LI S A   
e nz y me li n ke d i m m u n oassa y 
E O S  
 
E n d of St u d y  
E R T  
 
enz y me re place me nt thera p y  
E T V   
earl y t er mi nati o n visit  
F D A   
F o o d a n d Dr u g A d mi nistrati o n  
FI X  
 
Fact or I X  
F S H D   
faci osc a p ul o hu meral m usc ular d ystr o p h y  
G A G   
gl yc o sa mi n o gl yca n  
H B V   
he patitis B vir us  
H C C   
he pat o -cell ular carci n o m a  
H C V   
he patitis C vir us  
H D R   
h o m ol o g y -directe d re pair  
H E E N T  
hea d, e y es, ears, n ose, a n d t hr oat  
h FI X   
h u ma n Fact or I X   
HI V  
 
h u ma n i m m u n o deficie nc y vir us  
h I D U A 
h u ma n I D U A 
H S  
 
he para n s ulfate  
H S C T   
he mat o p oietic ste m cell tra ns pla nt ati o n  
I A R 
 
i nf usi o n-ass ociate d reacti o n  
I A T A  
I nter nati o nal Air Tra ns p ort Ass ociati o n   
I C H 
 
I nter nati o nal C ou ncil  fo r Har m o nisati o n   
I D U A  
i d ur o ni dase 
I E C 
 
i nstit uti o nal et hics c o m mittee 

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A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 2 2  of 8 6  
i P S C  
i n d uce d pl uri p ote nt ste m cells 
I R B 
 
i nstit uti o nal re vie w b oar d 
I T R 
 
i n verte d ter mi nal r e peat 
I V 
 
i ntra ve n o us 
J R O M  
j oi nt ra n ge of m oti o n 
L D H   
lactate de h y dr o ge nas e 
L T F U   
l o n g-ter m f oll o w-u p  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
M H R A  
Me dici nes a n d H ealt hcare P r o d ucts Re g ulat or y A ge nc y 
M P S I   
M uc o p ol ysacc h ari d osis I  
M P S I H  
H urler s y n dr o meg  
M P S I H S  
H urler -Sc h eie s y n dr o me  
M P S I S  
Sc heie s y n dr o me  
M RI  
 
ma g netic res o n a nce i ma gi n g  
m R N A   
messe n ger R N A  
N H EJ   
n o n -h o m ol o g o us e n d -j oi ni n g 
NI H  
 
Nati o nal I nstit utes of Healt h  
O H R   
Office f or H u ma n R esearc h  
P B S  
 
p h os p hate b uffere d s ali ne   
P C R  
 
p ol y merase c h ai n reacti o n  
P F T  
 
p ul m o nar y f u ncti o n test  
r A A V  
rec o m bi na nt A A V  
r A A V 2/ 6 
rec o m bi na nt A A V 2/ 6  
R N A   
ri b o n ucleic aci d 
R SI  
 
refere nce safet y i nf or mati o n  
S A E  
 
seri o us a d vers e e v e nt 
S M C   
Safet y M o nit ori n g  C o m mittee  
S M C H D 1  
str uct ural mai nte na n ce of c hr o m os o mes fle xi ble hi n ge d o mai n c o ntai ni n g 1 
S N P  
 
si n gle-n ucle oti de p ol y m or p his m  
S U S A R  
s us pecte d u ne x p ecte d seri o us a d verse reacti o n 
T E A E   
treat me nt-e mer ge nt A E   
U L N   
u p per li mit of n or mal  
V A B S -II 
Vi nela n d A da pti ve Be h a vi or Scales  
v g  
 
viral ge n o mes  
W A SI -II 
Wec hsler A b bre vi ate d Scale of I ntelli ge nce , Sec o n d E diti o n (S ha pir o et al. 2 0 1 5 ) 
W P P SI -I V 
Wec hsler Presc h o ol a n d Pri mar y Scale of I nt elli ge nce  
Z F N  
 
zi nc fi n ger n u cleas e  
Z F P  
 
zi nc fi n ger pr otei n  
6 M W T  
6 -mi n ute wal k test  

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A me n d me nt 7 1 2 D E C 2 0 1 9  
 
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1  
I N T R O D U C TI O N 
1. 1  
M uc o p ol ys acc h ari d osis I  
M uc o p ol ysacc h ari d osis t y pe I ( M P S I), als o referre d t o as H urler ( M P S I H)/ H urler-Sc heie  ( M P S 
HI S) / Sc heie ( M P S I S) s y n dr o me, is a recessi ve l ys os o mal st ora ge dis or der. Acc or di n g t o t he 
Nati o nal I nstit ute of Ne ur ol o gical Dis or ders a n d  Str o ke ( NI N D S) facts heet f or 
M P S I, t he 
esti mate d i nci de nce is  1 i n a b o ut 1 0 0, 0 0 0 birt hs  f or se vere M P S I, 1 i n a b o ut 5 0 0, 0 0 0 birt hs f or 
atte n uate d 
M P S I, a n d 1 i n a b o ut 1 1 5, 0 0 0 birt hs f or diseas e t hat falls bet wee n se vere a n d 
atte n uate d.  
M P S I is ass ocia te d wit h m utati o ns i n t he ge ne e nc o di n g t he i d ur o ni dase (I D U A) e n z y me, w hic h 
de gra des  gl yc os a mi n o gl yca ns (s ulfate d car b o h y drate p ol y mers; G A Gs). M utati o ns i n t he I D U A 
ge ne di mi nis h or eli mi nate I D U A e nz y me acti vit y, w hic h res ults i n t he acc u mulati o n of t o x ic 
G A G s i n uri ne a n d b o d y  tiss ues. 
De pe n di n g o n t he s pecifi c t y pe of I D U A m utati o n ( m ore  t ha n 1 0 0 differe nt m utati o ns ha ve bee n 
descri be d ) a n d t he le v els of t he res ulti n g resi d u al I D U A e n z y me acti vit y, patie nts will de vel o p 
eit her t he se vere M P S I H  or t he atte n uate d varia nts  M P S I H S a n d M P S I S . It has bee n esti mated  
t hat 5 0-8 0 % of all M P S I patie nts prese nt wit h t he se vere f or m  of t he disease  (M ue nzer  et al. 2 0 0 9 ). 
M P S I H  patie nts s h o w  s y m pt o ms of de velo p me ntal dela y bef ore t he e n d of t heir first year  of life , 
as well as halte d gr o wt h a n d pr o gressi ve me nt al decli ne bet wee n a ges 2 -4 y ears. Ot her s y m pt o ms 
i ncl u de or ga n o me gal y, c or neal cl o u di n g, j oi nt stiff ness, s keletal def or mities (i ncl u di n g a b n or mal 
s pi nal b o nes), c oarse facial feat ur es wit h e nlar g e d t o n g ue, heari n g l oss , a n d her nias. T he life 
e x pecta n c y of M P S I H p atie nts  is less t ha n 1 0 years.  
Patie nts wit h t he atte n uate d f or m s of t he disease s hare m ost of t hese cli nical ma nifestati o ns b ut  
wit h less se vere s y m pt o ms. I n a d diti o n, t here is n o ce ntral ner v o us s yste m ( C N S ) i n v ol ve me nt, 
a n d t heref ore M P S I H S a n d M P S I S patie nts d o n ot s uffer fr o m me ntal retar dati o n. Ma n y of t hese 
patie nts ca n s ur vi ve i nt o a d ult h o o d b ut wit h si g nifica nt m or bi dit y . 
C urre nt t hera pies f or M P S I i ncl u de he mat o p oie tic ste m cell tra ns pla ntati o n ( H S C T; usi n g b o ne 
marr o w or u m bilical c or d ste m cells) a n d e n z y me re place m e nt t hera p y ( E R T ; usi n g a p ol y m or p hi c 
rec o m bi na nt pr otei n pr o d uce d i n C hi nese Ha mster O var y cells, Al d uraz y m e).  
A l m ost all patie nts wit h M P S I H u n der g o H S C T. If p atie nts are dia g n ose d earl y (at < 2. 5  y ea rs), 
thera pe utic i nter ve nti o n b y H S C T  ca n pre ve nt or re verse m ost cli nical feat ures  i ncl u di n g t he 
ne ur oc o g niti ve s y m pt o ms . U nf ort u natel y, t he m ortalit y rate after H S C T h as bee n re p orte d t o be  
1 5 % , a n d s ur vi val rate wit h s uccessf ul e n graft me nt is 5 6 % , alt h o u g h rece nt i m pr o ve me nts i n 
H S C T pr oce d ure h a ve i m pr o ve d o verall o utc o mes  (B oele ns et al. 2 0 1 3 ).  
E R T has bee n s h o w n t o i m pr o ve p ul m o nar y f u ncti o n , he pat os ple n o me gal y,  a n d e xercis e ca pacit y , 
a n d t o lea d t o i m pr o ve d h ealt h-rel ate d q ualit y of life. E R T s h o ul d be i nstit ute d as earl y as p ossi ble. 
H o we ver, dra w bac ks of  E R T i ncl u de  the nee d f or life -l o n g treat me nt; de vel o p me nt of ne utralizi n g 
a nti b o dies;  i na bilit y t o cr oss t he bl o o d brai n barrier;  c o nti n ue d car di ac, ort h o pe dic,  a n d oc ular 
c o m plicati o ns ; a n d t he i nc o n ve nie nce of wee kl y i ntra ve n o us  (I V) i nf usi o ns. T hese dra w bac ks  
u n dersc ore t he ur g e nt ne e d t o de vel o p a br o a der arra y of c urati ve t h era pies f or M P S I . 
T he o bjecti ve a n d rati o n ale f or t he pr o p ose d S B -3 1 8 i n vesti gati o nal t hera p y is t o a br o gate or 
decrease t he nee d f or E R T  usi n g  i n viv o ge n o me e diti n g. T he pr o p ose d treat me nt e m pl o ys 
rec o m bi na nt a de n o-ass ociate d vir us (r A A V) c o m prisi n g e n gi neere d zi nc fi n ger n ucleases ( Z F Ns) 
t o site-s pecificall y i nte grate a c orrecti ve c o p y of t he h u ma n i d ur o ni dase e nz y me (h I D U A) 

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A me n d me nt 7 1 2 D E C 2 0 1 9  
 
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tra ns ge ne i nt o t he g e n o me of s u bjects’ o w n he pat oc ytes i n viv o. I nte grati o n of t he hI D U A 
tra nsge ne is tar gete d t o i ntr o n 1 of t he al b u mi n l oc us, res ulti n g i n sta ble, hi g h le vel, li ver -s pecifi c 
e x pressi o n a n d secreti o n of hI D U A  i nt o t he bl o o d. Place me nt of t he hI D U A tra ns ge n e u n d er t h e 
c o ntr ol of t he hi g hl y e x presse d e n d o g e n o us al b u mi n l oc us is e x pe cte d t o pr o vi de per ma n e nt, li ver -
s pecific e x pressi o n of hI D U A  f or t he lif eti me of a n M P S I patie nt. 
1. 2  
De vel o p me nt of Zi nc Fi n ger N ucle ases f or Ge n o me E diti n g  
Z F Ns are pr otei ns de vel o pe d f or ge n o me e dit i n g. T he y c o m bi ne t he D N A rec o g niti o n s pecificit y 
of zi nc fi n ger pr otei ns ( Z F P s) wit h t he n uclease  d o mai n  of t he  t y pe II S restricti o n e n d o n uclease 
F ok I t o create d o u ble stra n d brea k s ( D S Bs) at pre -deter mi ne d tar get site s i n t he ge n o me. Re pair of 
t he D S B s t y picall y lea ds t o t he i ntr o d ucti o n of m utati o ns t hat res ult i n f u ncti o nal k n oc k o uts of t he 
tar get ge ne pr o d ucts. 
Z F P s c o ntai n ta n de m arra ys of C ys 2 -His 2 zi nc fi n gers, eac h rec o g nizi n g a p pr o xi matel y 3 base 
pairs of D N A. T h e F ok I n uclease d o mai n  has n o se q ue nce s pecifi cit y , a n d m ust di merize t o c ut 
D N A.  C o nse q ue ntl y,  D N A  clea va g e acti vit y  is ac hie ve d b y 2  i n de pe n de nt Z F Ns c o nsisti n g of 
Z F Ps  directe d t o a djace nt se q ue nces i n t he c orrect s patial orie ntati o n (i.e., o n o p p osite si des of t he 
D N A wit h 5 or 6 base p airs  of se q ue n ce  bet w ee n t he rec o g niti o n sites ), eac h b o u n d t o a F ok I 
n uclease . 
Sa n ga m o  T hera p e utics , I n c. (Sa n g a m o ) has e n gi neere d a Z F N pair c o nsisti n g of a 5 -fi n ger 
( S B-4 7 1 7 1) Z F P a n d a 6 -fi n ger ( S B-4 7 8 9 8 ) Z F P  t hat bi n d wit h a n a djace nt 3 3  bas e pairs 
(c o m bi ne d) site o n i ntr o n 1 of t he h u m a n al b u mi n l oc us. F oll o wi n g t he D S Bs  create d b y t he F o kI  
n uclease d o mai n , t he D N A ca n be re paire d  b y eit her h o m ol o g y -directe d re p air  ( H D R) or 
n o n -h o m ol o g o us e n d -j oi ni n g ( N H EJ). T he c o -deli ver y of a D N A re p air te m plate e nc o di n g t he 
h I D U A tra ns ge n e f or i nserti o n at t he brea k ca n res ult i n t he tar gete d i nte grati o n of t he tra ns ge ne 
i nt o i ntr o n 1 of t he h u ma n al b u mi n l oc us  (see Fi g ure 1 ). 
 
Fi g ure 1 .  
Z F N -I n d uce d D S Bs Sti m ul ate T ar gete d I nte g r ati o n of a n A A V D o n or V i a 
N H E J or H D R . 
D S B
+ A A V d o n or
N H E J:
H D R - Dri v e n
T ar g et e d I nt e gr ati o n
H D R:
N H E J- Dri v e n
T ar g et e d I nt e gr ati o n
( E n d- C a pt ur e)
Al b u mi n i ntr o n 1
Z F N s

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
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A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 2 5  of 8 6  
1. 3  
P h ar m ac ol o g y  St u dies wit h S B -3 1 8  
1. 3. 1  I n Vitr o St u dies  
A series of st u dies usi n g  m o use pri mar y h e pat oc yt es or h u ma n pri mar y h e p at oc ytes a n d a h u ma n 
he pat o ma cell li ne  were c o n d ucte d t o de m o nstrat e t hat tra nsfecti o n wit h s pecies-s pecific al b u mi n 
Z F N s a n d hI D U A  D o n or  vect ors lea ds t o site-s pecific i nte grati o n at t he al b u mi n l oc us a n d  
e x pressi o n of acti ve hI D U A . E x pressi o n a n d s ecreti o n of acti ve h I D U A pr otei n was ass a ye d  b y 
I D U A E LI S A an d/ or e n z y matic acti vit y a nal ysis of cell c ult ure s u p er nata nts.  
1. 3. 1. 1  
P h ar m ac ol o gic Acti vit y i n M uri ne He p at oc ytes  
T he s urr o g ate m o use Z F Ns vect ors ( S B-4 8 6 4 1 + S B -3 1 5 2 3) a n d h I D U A D o n or  wit h m o use 
h o m ol o g y ar ms ( S B -m u -I D U A) were teste d i n pri mar y m o use he pat oc ytes i n vitr o. I D U A acti vit y 
was detect e d i n t he c ult ure s u per nat a nt at le vels of 0. 5 n m ol/ hr/ m L. 
1. 3. 1. 2  
P h ar m ac ol o gic Acti vit y i n H u m a n He p at oc ytes  
S B -3 1 8 was teste d  i n vitr o i n 3 h u ma n he pat oc yte s yste ms : pri mar y h u ma n h e pat oc ytes, pri mar y 
he pat oc ytes -d eri ve d fr o m h u ma n i n d uce d pl uri p ote nt ste m cells ( i P S C), a n d t he hu ma n he pat o ma 
cell li ne He p G 2. F oll o wi n g S B -3 1 8 tra ns d ucti o n, all  3  cell s yste ms d e m o nstrate d secreti o n of 
acti ve hI D U A i nt o t he c ult ure s u per nata nt.  
Cell  
I D U A Secreti o n ( n g/ m L) 
I D U A Acti vit y ( n m ol/ hr/ m L) 
Pri mar y He pat oc yt es  
8 2  
4  
i P S C– deri ve d  
1 0  
5  
He p G 2  
1 0 6  
4 5  
T hese res ults de m o nstrat e d t hat S B -3 1 8 ca n tr a ns d uce pri mar y h u ma n he p at oc ytes  a n d he p at o ma 
cells, a n d i n d uce t he e x pressi o n a n d secreti o n of acti ve hI D U A fr o m t he h u ma n al b u mi n l oc us.  
1 . 3. 2 I n Viv o St u dies  
T he i n viv o p har m ac ol o g y st u dies i ncl u de d  2  si n gle-d ose I V pr o of -of -c o nce pt p har mac ol o g y 
m o use st u dies i n w hic h t he A A V 2/ 8 m o use s urr o gate Z F Ns a n d hI D U A D o n or  were a d mi nistere d 
at a rati o of Z F N 1: Z F N 2: D o n or of 1: 1: 8 or 1: 1: 1 0, res pecti vel y, a n d a si n gle -d ose I V pil ot st u d y 
wit h r A A V 2/ 6 n o n -h u m a n pri mate s urr o gate Z F Ns a n d hI D U A D o n or  ( 1: 1: 8 rati o) c o m p o ne nts i n 
c yn o m ol g us m o n ke ys.   
1. 3. 2. 1  
P h ar m ac ol o gic Pr o of -of -C o nce pt i n C 5 7 B L/ 6 Mice  
M ale wil d -t y pe C 5 7 B L/ 6 mice ( ~ 8 -1 0 wee k ol d) were i njecte d wit h S B -4 8 6 4 1, S B -3 1 5 2 3,  a n d 
S B -m u -I D U A at t he i n dicate d d oses  ( Z F N + D o n or mice). C o ntr ol mice were i nject e d wit h t he 
S B -m u -I D U A D o n or  i n t he a bse nce of Z F Ns ( D o n or o nl y mice ).  
I n Z F N + D o n or mice , pl as ma I D U A acti vit y i ncrease d 4- t o 8-f ol d a b o ve n or mal p h ysi ol o gical 
le vels b y da y 1 4 p ost-i njecti o n relati ve t o le vels i n wil d -t y pe or D o n or o nl y mice ( s ee Fi g ure 2 ; 
Pa nel A ). Whe n tiss ues fr o m t hese mice were a nal yze d f or I D U A acti vit y, Z F N + D o n or mice 
dis pla ye d s u pra -p h ysi ol o gic le vels of I D U A acti vit y i n b ot h t he li ver ( w here it is pr o d uce d fr o m 
t he al b u mi n l oc us) a n d s plee n ( w here it is ta ke n u p fr o m t he plas ma) (see Fi g ure 2 ; Pa nels B -C ). 
T he I D U A acti vit y le vels o bser ve d were 1 0 -f ol d (li ver) a n d 4-f ol d (s plee n) a b o ve t he n or mal le vels 
of acti vit y see n i n wil d -t y pe a n d Do n or  o nl y mice. A d diti o nall y, tar gete d i nte grati o n of t he hI D U A 
D o n or  at t he m o use al b u mi n l oc us was c o nfir me d b y P C R a nal ysis of li ver ge n o mic D N A fr o m 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
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Pa ge 2 6  of 8 6  
t hese mice ( data n ot s h o w n). T his pr o of -of -c o nce pt st u d y de m o nstrate d  t he a bilit y of  t he 3  m o use 
s urr o gate vect ors t o i nte grate a n d e x press t he tra ns ge ne fr o m t he m o use al b u mi n l oc us i n t he li ver 
i n viv o. 
 
Fi g ure 2 .  
Z F N -dri ve n T ar geti n g of hI D U A t o M o use Al b u mi n I ntr o n 1 Res ults i n 
S u pr a p h ysi ol o gic al I D U A Acti vit y i n t he Li ver, Pl as m a , a n d S plee n of 
Wil d -ty pe Mice.  
C 5 7 B L/ 6 wil d -t y pe mice were I V i njecte d wit h 1. 2E + 1 2  v g of S B -m u -I D U A al o ne ( D o n or o nl y) or t o get her wit h 
1. 5 E + 1 1  of eac h S B -4 8 6 4 1  a n d S B-3 1 5 2 3 ( Z F N + D o n or) . U ntreate d wil d -t y pe mice were i ncl u de d as a d diti o nal 
c o ntr ols. I D U A e n z y matic acti vit y was assa y e d at t he i n dicate d ti me p oi nts i n t he plas ma ( A ), li vers (B ), a n d s plee ns 
(C ) of t hese mice . 
1. 3. 2. 2  
P h ar m ac ol o gic Pr o of -of -C o nce pt i n M P S I Mice  
T o de m o nstrate t he feasi bilit y of t his t hera pe utic a p pr oac h i n a rele va nt disease m o del, a st u d y was 
c o n d ucte d i n M P S I (I D U A k n oc k o ut) mice. T his m o del has bee n s h o w n t o e x hi bit p he n ot y pic 
feat ur es t y pical f or M P S I s u c h as cra ni of acial a b n or malities, ne ur ol o gical deficits, a n d i ncrease d 
G A G l e vels i n tiss ues a n d uri ne. T his m o del has bee n s uccessf ull y use d t o st u d y E R T a n d A A V -
me diate d ge ne t hera p y (Hart u n g et al. 2 0 0 4; O u et al. 2 0 1 4 ). I n t his st u d y, 4 m o nt h ol d male a n d 
fe male M P S I mice were i njecte d wit h S B -4 8 6 4 1, S B -3 1 5 2 3 , a n d S B -m u -I D U A at t he i n dicate d 
d oses  ( Z F N + D o n or mice). C o ntr ol  mice were  i njecte d wit h S B -m u -I D U A i n t he a bse nce of Z F Ns 
( D o n or o nl y mice ).  
T he m o use al b u mi n  Z F N acti vit y was deter mi ne d b y dee p se q ue nci n g of t h e m o use al b u mi n l oc us 
at b ot h da y 2 1 a n d da y 6 0 ( necr o ps y). W h ereas  b ot h t he u ntreate d a n d D o n or  o nl y mice s h o we d 
n o si g nifica nt si g nal, t he Z F N + D o n o r mice s h o we d a ra n ge of 1 3 -5 0 % i n dels at t he al b u mi n l oc us 
( data n ot s h o w n). I n Z F N + D o n or  mice, plas m a I D U A e n z y matic acti vit y was clearl y i ncrease d 
relati ve t o t he D o n or o nl y mice  (see Fi g ure 3 ; Pa nel A). Plas ma I D U A acti vit y i n t hese mice 
re mai ne d ele vate d t hr o u g h o ut t he d urati o n of t he st u d y, a n d reac h e d t he le vels of c o ntr ol mice t hat 
were  h eter o z y g o us f or t he I D U A g e ne b y d a y 1 4 ( see Fi g ure 3 ; Pa nel A, das he d li ne). Mic e 
recei vi n g Z F N + D o n or dis pla ye d le vels of I D U A acti vit y i n t he li ver e q ui vale nt t o a n d e xcee di n g 
mice heter oz y g o us f or t he I D U A ge n e (see Fi g ur e 3 ; Pa nel B ). F urt her, el e vated I D U A acti vit y 
was als o d etecte d i n t he s plee n, ki d ne y, a n d l u n gs c o m pare d t o b ot h u ntr eate d M P S I mice a n d 
D o n or o nl y mice (see Fi g ure 3 ; Pa nel C ). T hese data s u p p ort t hat Z F N-dri ve n i nte grati o n of t h e 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 2 7  of 8 6  
hI D U A ge ne at t he m o use a l b u mi n l oc us i n t he li ver in viv o  lea ds t o t he e x pressi o n a n d secreti o n 
of hI D U A i nt o t he plas ma, w here it is s u bse q ue ntl y ta ke n u p b y sec o n d ar y tiss ues i n a n acti ve 
f or m.  
 
Fi g ure 3 .  
Z F N -dri ve n T ar geti n g of hI D U A t o M o use Al b u mi n I ntr o n 1 Res ults i n Hi g h 
Le vels of I D U A Acti vit y i n t he Li ver, Pl as m a, a n d Tiss ues of M P S I Mice.  
A d ult M P S I mice were i njecte d wit h 1. 5 E + 1 2  v g of S B -m u -I D U A ( D o n or o nl y) or wit h 1. 5E + 1 1  of eac h S B -4 8 6 4 1 
a n d S B-3 1 5 2 3 ( Z F N + D o n or). ( A ) Plas ma was c ollecte d at t he i n dicate d ti me p oi nts a n d assa ye d f or I D U A e nz y matic 
acti vit y. Das he d li ne i n dicates le vels of I D U A acti vit y i n u ntreate d heter oz y g o us mice. ( B  a n d C ) At necr o ps y ( da y 
6 0), tiss ues fr o m eac h gr o u p, al o n g wit h u ntreate d heter oz y g o us a n d M P S I disease c o ntr ol mice, were assa y e d f or 
I D U A e n z y matic acti vit y. 
T o assess t he f u ncti o nal i m pact of t his i ncrease i n I D U A e x pressi o n a n d acti vit y,  le vels of G A G s 
were me as ure d. T h e G A G s he para n  s ulfate ( H S) a n d der mata n s ulf ate  ( D S) are t he pri mar y 
s u bstrates of I D U A i n viv o, a n d acc u m ulate i n t he or ga ns of b ot h M P S  I patie nts a n d I D U A 
k n oc k o ut mice (M ue nz er et al. 2 0 0 9; O u et al. 2 0 1 4 ). I n u ntreate d M P S I mice a n d D o n or o nl y 
mice, G A G  le vels were el e vate d i n t h e uri ne  (see Fi g ure 4 ; Pa n el A). I n c o ntr ast, Z F N + D o n or mice 
dis pla ye d re d uce d uri nar y G A G le vels i n disti n g uis ha ble fr o m heter o z y g o us c o ntr ol mice. Re d uce d 
G A G  le vels were als o o bser ve d i n se veral tiss ues fr o m t hese mice relati ve t o b ot h u ntreate d M P S 
I a n d Do n or o nl y mice, i n dicati n g f u ncti o nal c orrecti o n of I D U A e n z y me e x pressi o n a n d acti vit y  
i n a br oa d arra y of tiss ues (see Fi g ure 4 ; Pa nel B). 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 2 8  of 8 6  
 
Fi g ure 4 .  
Z F N -dri ve n hI D U A E x pressi o n Res ults i n Re d ucti o n of G A G i n Uri ne a n d 
Tiss ues.  
Uri ne was c ollecte d at da ys 2 1 a n d 6 0, a n d tiss ues were c ollecte d at da y 6 0. Le vels of G A Gs were deter mi n e d i n t he uri ne ( A ) a n d 
tiss ues (B ) of t h e mice b y a d ye-bi n di n g assa y. G A G le vels were si g nifica ntl y re d uce d i n all a nal yze d tiss ues fr o m Z F N + D o n or 
mice, as  c o m pare d t o u ntreate d M P S I mice ( P < 0. 0 2; 2 -taile d Ma n n-W hit ne y test).  
I n s u m mar y, t his pr o of-of -c o nce pt st u d y de m o nstrate d t hat: 1) c o -d eli ver y of t he m o use s urr o gate 
Z F Ns a n d S B -m u -I D U A D o n or  lea ds t o hi g h le vels of I D U A e x pressi o n a n d acti vit y i n t he li ver; 
2) I D U A e x presse d fr o m t he a l b u mi n l oc us i n t h e li ver is secrete d i nt o t he plas ma i n a n acti ve 
f or m; 3) secrete d I D U A is ta ke n u p b y sec o n dar y tiss ues; a n d 4) s u bse q ue nt I D U A acti vit y i n t hese 
tiss ues is s ufficie nt t o c orrect t he meta b olic defect i n M P S I mice. T hese res ults s u p p ort t he 
feasi bilit y of usi n g S B-3 1 8 f or t he p he n ot y pic c orrecti o n of I D U A deficie nc y i n M P S  I patie nts . 
F or a d diti o nal p har mac ol o g y a n d t o xic ol o g y st u dies, refer t o t he I n v esti gat or Br oc h ure. 
1. 4  
Cli nic al E x perie nce wit h Zi nc Fi n ger N ucle ases  
T his is a first-i n-h u ma n st u d y f or S B -3 1 8 .  
As of 1 1 Se pte m ber 2 0 1 8, o ne s u bject wit h 
M P S I has recei ve d S B -3 1 8 at a d ose of 
1. 0 0 E + 1 3  v g/ k g. T he s u bject t olerate d t he i nf usi o n well a n d re p orte d n o a d verse e ve nts as of 
7  wee ks p ost i nf usi o n.. ( F or f urt her det ails, see Secti o n 8. 1 ). 
A Z F N -me diate d i n viv o ge n o me e diti n g P has e I st u d y f or M P S II is o n g oi n g ( S B -9 1 3 -1 6 0 2).  T h e 
st u d y treat me nt, S B -9 1 3, is a r A A V 2/ 6-bas e d g e ne tra nsfer a ge nt t hat c o m prises  t he i de ntical 
Z F N s as S B -3 1 8 (na m el y, S B -4 7 1 7 1 a n d S B -4 7 8 9 8) , b ut differs fr o m S B-3 1 8 wit h res pect t o t he 
d o n or c D N A ( w hic h i n S B -9 1 3 e nc o des  h u ma n i d ur o nate -2 -s ulf atase). As of 1 1 Se pte m ber 2 0 1 8, 
6 a d ult s u bjects wit h M P S II ha v e recei ve d S B-9 1 3 at d oses of u p t o 5. 0 0 E + 1 3 v g/ k g. S B -9 1 3 w as 
well t olerate d, a n d re p ort e d A Es were m ostl y mil d ( Gra de 1) i n se verit y a n d u nrelate d t o t he st u d y 
treat me nt.  
F o ur s u bjects re p orte d A Es assesse d as relate d t o S B -9 1 3 b y t he Pri nci pal I n v esti gat or. T he A Es 
i ncl u de d fl us hi n g i n a s u bject 3 da ys after d osi n g; fl us hi n g a n d er yt h e ma i n a s u bject o n t he da y 
of d osi n g, a n d A L T a n d  A S T i ncrease d i n t his s a me s u bject 6 0 d a ys after d osi n g; c ol d s weat, 
dizzi ness, a n d ast he nia i n o ne s u bject 4  da ys after d osi n g; a n d 2 e ve nts of pr urit us i n a s u bject 2 
a n d 6 da ys after d osi n g. Eac h of t hese e ve nts was mil d ( Gra de 1) i n se v erit y, a n d res ol ve d wit h o ut 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 2 9  of 8 6  
treat me nt. N o persiste nt tra nsa mi nitis ha s bee n o bser ve d i n a n y s u bject after S B-9 1 3 i nf usi o n as 
of t he data c ut off date.   
N o S A Es assesse d as relate d t o S B -9 1 3 were re p orte d. T w o S A Es were re p orte d i n 2 s u bjects, a n d 
eac h w as assess e d  b y t he Pri nci pal I n vesti gat or  as n ot relate d t o S B -9 1 3 b ut rat her sec o n dar y t o 
t he s u bjects’ u n derl yi n g M P S II disease . A n S A E of ac ute br o nc hitis was re p orte d a p pr o xi matel y 
3 wee ks aft er S B -9 1 3 i nf usi o n i n a s u bject wit h a hist or y of c hr o nic o bstr ucti ve p ul m o nar y disease 
( C O P D) f or w hic h t he s u bject was si milarl y h os pitalize d 2 y ears pri or, trac he o br o nc h o malacia, 
a n d slee p a p nea. A n S A E of atri a l fi brillati o n was re p orte d a p pr o xi matel y 7 wee ks aft er S B-9 1 3 
i nf usi o n i n a s u bj ect wit h a hist or y of mitral v al ve ste n osis, p ul m o nic val ve ste n osis, a ortic 
ste n osis, left atrial e nlar g e me nt, a n d heart pal pitati o ns. 
A n ot her cell t hera p y m o difie d b y Z F Ns, S B -7 2 8 -T , has bee n a d mi nistere d t o date t o o v er 
7 0  s u bjects wit h HI V i nfecti o n  i n 4 P hase I st u dies: o ne  st u d y s p o ns ore d b y t he U ni versit y of 
Pe n ns yl va nia , a n d t he ot her 3  st u dies s p o ns ore d b y Sa n ga m o . S B -7 2 8 -T is a ut ol o g o us e nri c he d 
C D 4 + T -cells t hat h a ve  b ee n tr a ns d uce d ex vi v o  wit h Z F Ns , res ulti n g i n m o dificati o n of t h e C C R 5 
ge ne. A d o n or tra ns ge ne was n ot c o -i nf use d wit h t his t hera p y. T he Z F Ns we re deli vere d wit h a 
re plicati o n defi cie nt rec o m bi na nt A d 5/ 3 5 viral vect or  (a n d s u bse q ue ntl y b y electr o p orati o n of 
m R N A ), w hic h t hr o u g h tra nsi e nt e pis o mal e x pressi o n deli vere d  t hes e n u cleases t o tra ns d uce d 
cells. T he 2  Z F Ns bi n d t o a c o m p osite 2 4 -b ase p air se q ue nce f o u n d s pecificall y i n t he re gi o n 
e nc o di n g t he first tra ns me m bra n e d o mai n of t h e C C R 5 ge ne, j ust u pstrea m fr o m t he n at urall y 
occ urri n g C C R 5  delta 3 2 m utati o n. E x pressi o n of t he C C R 5 -s pecific Z F Ns i n d uces a D S B  t hat is 
re pair e d. In a p pr o xi matel y 3 0 % of tra ns d uce d cells t he re pair lea ds t o t h e i nserti o n of ra n d o m 
se q ue nces or deleti o ns t h at disr u pt t he C C R 5 c o di n g se q ue n ce , l ea di n g t o fra me s hift m utati o ns 
a n d ter mi nati o n of C C R 5 pr otei n e x pressi o n.  S B -7 2 8 -T i nf usi o ns were  well t olerate d wit h m ost l y 
mil d a n d m o derate re versi ble i nf usi o n-relate d A Es . T he m ost c o m m o n A Es wer e s ki n o d or 
a b n or mal (ca us e d b y t he D M S O re q uire d f or cell  freezi n g), fati g ue, u p per res pir at or y tract 
i nfecti o n, hea dac h e, c hills, fe ver, a n d  p yre xia . S A Es were re p orte d i n 3  s u bjects: 2 s u bjects 
e x perie n ce d S A Es assess e d as u nrel ate d t o S B -7 2 8 -T  (i ncl u din g a n e ve nt of p ol ys u bsta nce a b us e 
lea di n g t o u nres p o nsi ve ness i n a s u bject wit h a hist or y of s u bsta nce a b use, a n d a n e v e nt of 
cell ulitis/ M R S A a bscess i n a s u bject wit h a s us pecte d hist or y of i ntra ve n o us dr u g a b use ); a n d 1 
s u bject e x perie nce d S A Es of fe ver, c hills, j oi nt pai n, a n d bac k pai n 1  da y aft er S B -7 2 8 -T i nf usi o n, 
w hic h were attri b ute d t o a n i nf usi o n reacti o n a n d assesse d as relate d t o t he st u d y treat me nt. 
T here h a ve bee n n o re p orts of mali g na nc y i n a n y of t hese st u dies as of 1 1 S e pte m ber  2 0 1 8 . 
1. 5  
D ose J ustific ati o n  
T he selecti o n of 1 . 0 0 E +1 3  v g/ k g as t he pr o p ose d cli nical starti n g d ose of S B -3 1 8 ta kes i nt o 
acc o u nt 2  critical o bje cti ves: 1) a d mi nistrati o n of s ufficie nt a m o u nts of t h e 3  S B -3 1 8 A A V vect ors 
t o e nter t he h e pat oc ytes, tra ns d uce t he cells , e x press hI D U A , a n d pr o vi de  hi g h e n o u g h le vels of 
b ot h Z F Ns t o i n d uce D S B s i n t he cells; a n d 2) cli nical safet y data fr o m st u d y S B -9 1 3 -1 6 0 2, i n 
w hic h a d mi nistrati o n of a l o wer d os e of 5. 0 0 E + 1 2 v g/ k g of t he hi g hl y si milar S B -9 1 3 st u d y 
treat me nt was g e nerall y well-t olerate d i n t he 2 s u bjects t hat were d ose d. 
Precli nical data fr o m Sa n ga m o ’s S B-FI X pr o gra m s u p p orts a mi ni mal effecti ve si n gle Z F N d ose 
eac h of 1. 2 0 E + 1 3  v g/ k g t o e ns ure a de q u ate n uclease acti vit y f or i nserti o n of t he h u ma n Fact or I X 
( h FI X) c D N A d o n or i nt o t he tar get site a n d yiel d  circ ulati n g  h FI X le vels of a b o ut 1 % n or mal. T he 
pr o p ose d S B -3 1 8 starti n g d ose of 1. 0 0 E + 1 3 v g/ k g is t heref ore e x pecte d t o be c o m para ble t o t he 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 3 0  of 8 6  
mi ni mall y -effecti ve d ose i n a ni mal st u dies . Cli nicall y si g nifica nt le vels of hI D U A are e x p ecte d t o 
be o bser ve d  at S B -3 1 8 d ose le vels of 1 . 0 0 E +1 3 v g/ k g a n d 5. 0 0 E + 1 3 v g/ k g . 
D osi n g is f urt her i nf or m e d b y t he c u m ulati ve st u d y data o n 6 s u bjects w h o recei ve d  t he hi g hl y 
si milar S B -9 1 3 st u d y treat me nt at 3 differe nt d oses t hat 
was re vie we d b y t he S M C o n 
0 8  Oct o ber  2 0 1 8. Bas e d o n t hese data, t h e S M C rec o m me n de d t he f oll o wi n g f or t he S B-9 1 3 st u d y: 
e x pa nsi o n of t he 5. 0 0 E + 1 3 v g/ k g d ose c o h ort a n d o pe ni n g of t he first pe diatric c o h ort wit h d osi n g 
at 5. 0 0 E + 1 3 v g/ k g , as well as c o nsi derati o n of a hi g her d ose (see Secti o n 8. 1 f or a d diti o nal details). 
T he S M C f or t his st u d y ( S B -3 1 8 -1 5 0 2) re vie we d data acr oss b ot h pr o gra ms o n 0 8 Oct o ber 2 0 1 8 
a n d rec o m me n d e d c ha n gi n g t he e nr oll me nt of C o h ort 1 fr o m 2 s u bjec ts t o 1 s u bject, a n d o pe ni n g 
e nr oll me nt of C o h ort 2 at 5. 0 0 E + 1 3 v g/ k g  t o i m pr o ve t he be nefit/ris k f or s u bjects. 
T he sele cti o n of 1. 2 0 E + 1 4  v g/ k g as t he hi g hest  d ose of S B -3 1 8  i n C o h ort 3  is bas e d o n d ata 
o btai ne d i n precli nical st u dies i n w hic h A A V 2/ 6 Z F N a n d c D N A d o n or were a d mi nistere d t o mice 
a n d c y n o m ol g us m o n ke ys at d ose le vels u p t o 1. 5 0 E + 1 4 v g/ k g. N eit her i n crease i n li ver e nz y m es 
n or a d verse micr osc o pic fi n di n gs were o bser ve d i n t he mice. Tra nsie nt i ncreases i n li ver e n z y mes, 
as well as mil d, ge neral l y re versi ble, he p atic i nfla m mati o n, li kel y relate d t o t he e x presse d h u ma n 
pr otei n a n d/ or A A V v ect or, were o bser ve d i n t he c y n o m ol g us m o n ke ys. T he safet y res ults fr o m 
t hese n o ncli nical st u dies t h us s u p p ort h u ma n d osi n g of S B-3 1 8  at u p t o 1. 2 0 E + 1 4 v g/ k g, w hic h 
pr o vi des a 1. 2 5 -f ol d d os e m ulti ple t o t he hi g hest teste d d ose i n c y n o m ol g us m o n ke ys. 
I n a d diti o n t o Sa n ga m o’s st u dies, ot her cli nical trials usi n g A A V-bas e d ge ne t hera p y  ha v e 
pr o vi de d e vi de nce t hat a t otal A A V d ose of u p t o 2. 0 0 E + 1 4  v g/ k g ca n be a d mi nistere d t o h u ma ns 
wit h a n acce pta ble safet y pr ofile ( Me n d ell et al. 2 0 1 7 ).  
1. 6  
T ar gete d P atie nt P o p ul ati o n  
T he tar get e d patie nt p o p ulati o n of t his st u d y will be patie nts wit h  M P S  I. S u bjects will be 
se q ue ntiall y e nr olle d i n a ge c o h orts: a g e > 1 8 (a d ult c o h orts 1 t hr o u g h 3), a ge 1 2 -1 7 ( pe diatric 
c o h orts 4 a n d 5), a n d a ge 5 -1 1 ( pe di atric c o h orts 6 a n d 7). T h e pe diatric c o h orts will be e nr olle d 
o nl y after re vie w of c u m ulati ve a d ult safet y data b y a n i n de pe n d e nt, e xter nal Safet y M o nit ori n g 
C o m mittee ( S M C).  
C urre ntl y, t h e treat me nt of c h oice f or t his patie nt p o p ulati o n is E R T usi n g Al d uraz y me. E R T has 
bee n s h o w n t o i m pr o ve s o matic ma nifestati o ns i ncl u di n g wal ki n g ti me, he pat os ple n o me gal y , a n d 
restricti ve l u n g c o m plicati o ns of t he diseas e. It has pr o ve n i neffecti ve, h o we ver, i n a d dressi n g t he 
C N S i n v ol ve me nt ( d ue t o t he i na bilit y of t he e nz y me t o cr oss t h e bl o o d brai n barrier), t he 
pr o gressi ve j oi nt a n d ort h o pe dic c o m plicati o ns, t he car diac pr o ble ms, a n d t he c or neal cl o u di n g. 
F urt her dra w bac ks i n cl u de the nee d f or life -l o n g treat me nt, de v el o p me nt of ne utr alizi n g 
a nti b o dies, a n d t he i nc o n ve nie nce of wee kl y I V i nf usi o ns. 
S B -3 1 8 is e x pecte d t o pr o vi de life-l o n g, li ver-s pecific e x pressi o n of hI D U A .  
1. 7  
Ris k Be nefit Assess m e nt a n d St u d y H y p ot hesis  
M P S  I is a recessi ve l ys os o mal st ora ge dis or der t h at res ults fr o m m utati o ns i n t he g e ne e nc o di n g 
I D U A. D eficie n c y or decreased  l e vels of t he e n z y me res ults i n t he acc u m ul ati o n of t o xic le vels of 
meta b oli tes s uc h as G A G s i n uri ne, bl o o d , a n d b o d y tiss ues. Cli nical se verit y of M P S I vari es 
de pe n di n g o n resi d ual I D U A acti vit y . 
T he o bjecti ve f or t he pr o p ose d S B-3 1 8 i n vesti gati o nal t hera p y is t o a br o gat e or decrease t he nee d 
f or E R T b y i n viv o ge n o me e diti n g. T he pr o p ose d treat me nt e m pl o ys e n gi neere d Z F Ns t o 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 3 1  of 8 6  
site-s pecificall y i nte grate a c orrecti ve c o p y of t he hI D U A tr a ns ge ne i nt o t h e ge n o me of a s u bject’s 
o w n he pat oc yt es i n viv o. I nte grati o n of t h e hI D U A tra ns ge ne is tar gete d t o i ntr o n 1 of t he al b u mi n 
l oc us, res ulti ng i n sta ble, hi g h le vel, li ver -s pecific e x pressi o n a n d secreti o n of hI D U A  i nt o t h e 
bl o o d. Place me nt of t he hI D U A tra ns g e ne u n der t he c o ntr ol of t he hi g hl y e x presse d e n d o ge n o us 
al b u mi n l oc us is e x pecte d t o pr o vi de per ma n e nt, li ver -s pecifi c e x pressi o n of hI D U A  f or t he 
lifeti me of a n M P S I p atie nt a n d i m pr o ve c urre nt cli nical o utc o mes of E R T or H S C T t hera p y . 
T he  maj or  ris k of t hera p y wit h S B -3 1 8 , w hic h is pres u me d A A V ca psi d pr otei n i m m u n o ge nicit y, 
a n d p ossi ble i m m u n ol o gical res p o ns es i n v ol vi n g t he e x presse d h I D U A i n t he li ver p ost -i nf usi o n, 
w ill be cl osel y m o nit ore d i n t his st u d y (see Secti o n  8 ). A n i m m u ne res p o nse is li kel y t o be 
ge nerat e d t o A A V ca psi d pr otei n bas e d u p o n pr e vi o us ge ne t h era p y st u dies i n He m o p hilia, b ut ca n 
be a meli orate d w it h a s hort c o urse of ster oi ds. W het her a n i m m u ne res p o nse will de vel o p a gai nst  
h I D U A re mai ns t o be deter mi ne d. M ost M P S I p atie nts ( 9 7%) recei vi n g E R T wit h Al d uraz y me 
de vel o p  I g G a nti b o dies t o α -L -i d ur o ni d ase. H o we ver, Al d uraz y m e  is a p ol y m or p hic varia nt of 
hI D U A  t hat is pr o d uce d i n C hi nese Ha mster O var y cells. T heref ore, it is u n k n o w n if a nti b o dies 
will de vel o p a gai nst  t he hI D U A d eli vere d b y S B-3 1 8 , w hic h will ha v e a gl yc os ylati o n patter n 
deri ve d fr o m h u ma n h e p at oc ytes .   
A n ot her  p ote ntial ris k is t he effect o n al b u mi n s y nt hesis. H o we ver,  gi ve n t he i ntr o nic l ocati o n of 
t he Z F N tar g et site a n d t hat < 1 % of  al b u mi n l oci i n e x pressi n g h e pat oc yt es  are pre dicte d t o be 
disr u pte d, S B -3 1 8  s h o ul d ha ve a mi ni mal cli nical i m pact o n o verall h e p atic al b u mi n pr o d ucti o n.  
A n ot her p ote ntial ris k is t he off -tar get m o difi cati o n at t he str u ct ural mai nte na nce of c hr o m os o mes 
fle xi ble hi n ge d o mai n c o ntai ni n g 1 (S M C H D 1 ) l oc us. T his is n ot e x pecte d gi ve n t hat n o off -tar get 
acti vit y has bee n o bser ve d at cli nicall y rele va nt le vels of al b u mi n o n -t ar get acti vit y i n h u ma n cells 
i n vitr o (see Secti o n 8. 1. 2 ). 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 3 2  of 8 6  
2  
S T U D Y O B J E C TI V E S  
2. 1  
Pri m ar y O bjecti ves  
•  T o e val uate t he s afet y a n d t olera bilit y of S B -3 1 8 . 
2. 2  
 Sec o n d ar y O bjecti ves  
•  T o e val uate c ha n ge fr o m B aseli ne o ver ti me i n t he f oll o wi n g assess me nts :  
o  I D U A acti vit y i n bl o o d. 
o  G A G  testi n g i n uri ne. 
o  Fre q u e nc y  of E R T a d mi nistrati o n.  
•  T o e val uate A A V cle ara nce  
2. 3  
E x pl or at or y O bjecti ves  
•  T o e val uate c ha n ge fr o m B aseli ne o ver ti me i n t he f oll o wi n g assess me nts : 
o  G A G le vels i n tiss ues (i n cl u di n g bl o o d, li ver tiss ue, a n d cere br os pi nal fl ui d [ C S F]).  
o  Ge ne m o dificati o n at t he al b u mi n l oc us i n t he li ver.  
o  I ma gi n g, f u ncti o nal, a n d ne ur oc o g niti ve testi n g rel ate d t o M P S I. 
o  I m m une res p o nse t o A A V 2/ 6 , Z F Ns , a n d I D U A. 
Fr o m c o nse nti n g s u bjects, resi d ual sa m ples ma y be use d f or f ut ure res earc h o bjecti ves. S uc h f ut ure 
researc h o bj ecti ves ma y i ncl u de a n al ysis of bi o mar kers  of se verit y of dise ase, res p o nse t o t hera p y 
(e. g., c yt o ki nes, s ol u ble cell s urface pr otei ns,  s ol u ble rece pt ors), a n d f u ncti o nal i m pr o ve me nts 
(e. g., ne ur ol o gical f u ncti o n, m usc ul os keletal f u ncti o n), as well as deter mi nati o n of A A V vir us 
i n hi biti o n, f u ncti o n, i m m u n o ge nicity , or p h ar mac o d y na mics (e. g., a nti b o dies, s ol u ble rece pt ors, 
A A V vir al rece pt or i n hi bit ors, c yt o ki nes, c o-e xisti n g alter nate ser ot y p e a nti b o dies).  F or m or e 
details , refer t o t he St u d y Refere n ce M a n ual.  
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 3 3  of 8 6  
3  
S T U D Y D E SI G N  
3. 1  
O ver vie w  
T his is a P hase 1/ 2 , m ultice nter, o pe n -l a bel, si n gle-d ose, d ose -ra n gi n g st u d y wit h se q ue ntiall y 
e nr olle d a g e c o h orts: a ge > 1 8 (a d ult c o h orts 1 t hr o u g h 3), a g e 1 2 t o 1 7 ( pe di atric c o h orts  4  a n d 5 ), 
a n d a ge 5  t o 1 1 ( pe diatric c o h orts 6  a n d 7 ). S u bjects w h o satisf y all i ncl usi o n/e xcl usi o n criteria are 
eli gi ble t o partici pate i n t his s t u d y.  
3. 2  
N u m ber of S u bjects  
U p t o a t otal of 2 7  s u bjects ma y be e nr olle d i n t his st u d y.  
3. 3  
D ose  
T he d ose s of S B -3 1 8  sele cte d f or e val uati o n i n t his st u d y are: 
C o h ort  
Z F N 1 ( S B -4 7 1 7 1)  
( v g/ k g) 
Z F N 2 ( S B -4 7 8 9 8)  
( v g/ k g) 
hI D U A  D o n or ( S B -
I DU A )  
( v g/ k g) 
T ot al r A A V  
( v g/ k g) 
1  
1. 0 0 E + 1 2  
1. 0 0 E + 1 2  
8. 0 0 E + 1 2  
1. 0 0 E + 1 3  
2  
5. 0 0 E + 1 2  
5. 0 0 E + 1 2  
4. 0 0 E + 1 3  
5. 0 0 E + 1 3  
3  
1. 2 0 E + 1 3  
1. 2 0 E + 1 3  
9. 6 0 E + 1 3  
1. 2 0 E + 1 4  
4  
T B D  
T B D  
T B D  
T B D  
5  
T B D  
T B D  
T B D  
T B D  
6  
T B D  
T B D  
T B D  
T B D  
7  
T B D  
T B D  
T B D  
T B D  
 
3. 4  
St u d y D ur ati o n  
T he d urati o n of st u d y partici pati o n f or eac h s u bject will be a p pr o xi matel y 3 9  m o nt hs (see 
Fi g ure  5 ), di vi de d i nt o a p pr o xi matel y 3 m o nt hs f or S cree ni n g  f oll o we d b y 3 6  m o nt hs f or treat me nt 
a n d st u d y f oll o w -u p .  
 
Fi g ure 5 .  
Sc he m a of St u d y Visits . 
 
U p o n c o m pleti o n of t he st u d y, s u bjects will  be as ke d t o partici pate i n a se parate L o n g-ter m 
F oll o w -U p ( L T F U) S t u d y t o m o nit or t he l o n g-ter m safet y of S B -3 1 8 . T o alle viate st u d y b ur de n, 
st u d y s u bjects ma y p arti ci pate i n t h e L T F U St u d y after at least 1 2 m o nt hs of f oll o w -u p i n t his 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 3 4  of 8 6  
st u d y. St u d y partici pa nts w h o wis h t o e nr oll i n t he LT F U St u d y wit h less t ha n 1 2 m o nt hs of f oll o w -
u p i n t his pri mar y st u d y  ma y be c o nsi dere d o n a case -b y -case basis at t he j u d ge me nt of t he 
Pri nci pal I n v esti g at or a n d after c o ns ultati o n wit h t he S p o ns or.  
3. 5  
St u d y  Sc he d ule  
S u bjects w h o satisf y all eli gi bilit y  criteria will be e nr olle d i nt o o n e of t h e f oll o wi n g treat me nt 
c o h orts as descri be d bel o w : 
C o h ort #  
A ge R a n ge 
( y) 
T ot al D ose 
( v g/ k g) 
# S u bjects  
1  
≥1 8  
1. 0 0 E + 1 3  
1  
2  
≥1 8  
5. 0 0 E + 1 3  
2  
3  
≥1 8  
1. 2 0 E + 1 4  
2  
4  
1 2 -1 7  
T B D  
2  
5  
1 2 -1 7  
T B D  
2  
6  
5 -1 1  
T B D  
2  
7  
5 -1 1  
T B D  
2  
F or eac h d ose c o h ort after C o h ort 1, t w o s u bjects will be d ose d at least 4 wee ks a p art  (see 
Fi g ure  6 ). S M C re vi e w will occ ur aft er all s u bjects i n eac h c o h ort h a ve ≥ 4 wee ks of s afet y dat a. 
T he pe diatri c c o h orts will be e nr olle d o nl y aft er re vie w of c u m ulati ve a d ult s afet y dat a  b y t he S M C 
(see Secti o n 1 2 . 3). T he starti n g d ose f or pe diatric c o h orts 4  t hr o u g h 7 will be deci de d base d o n 
S M C re vie w of st u d y dat a, a n d m ust meet pre-defi ne d safet y criteria (see P e diatric D osi n g).  
A p pr o xi matel y 2 a d diti o nal s u bjects ma y be a d d e d t o a n y a ge c o h ort  after S M C re vie w  of st u d y 
data if safet y criteria are met (see Safet y M o nit ori n g C o m mittee), wit h u p t o a t otal of 2 7  s u bjects 
i n t he st u d y. 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 3 5  of 8 6  
 
Fi g ure 6 .  
Sc he m a of S B -3 1 8 -1 5 0 2 C o h ort E nr oll me nt.  
Bl ue b o x = a d ult s u bjects a g e ≥1 8 years; p ur ple b o x = pe diatric s u bjects a ge 1 2 -1 7; gree n b o x = pe diatric s u bjects a g e 
5 -1 1; ora n ge b o x = S M C re vie w; das he d ora n ge li ne = S M C rec o m me n dati o n o n pe diatric d osi n g . 
S u bjects w h o recei ve d E R T pri or t o st u d y e nr oll me nt will c o nti n ue t o recei ve E R T d uri n g t he 
st u d y a n d re mai n o n t heir c urre nt sc he d ul e per sta n dar d of care u nless  t he y u n der g o 
pr ot oc ol -s pecifi e d E R T wit h dra wal p er pr ot o c ol  (see Secti o n 1 1. 4 ). H o we v er, E R T will be o mitte d 
d uri n g t he wee k  of t he S B -3 1 8  i nf usi o n t o facilitate acc urate baseli ne testi n g  (e. g., of G A G le vels 
i n uri ne, bl o o d, a n d of I D U A  acti vit y  i n bl o o d ) a n d t o all o w a wee k free of E R T after t he S B-3 1 8  
i nf usi o n. 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 3 6  of 8 6  
T o mi ni mize t he p ot e ntial i m m u ne res p o nse t o t he A A V ca psi d pr otei n, t he e n gi ne ere d Z F Ns, or 
t he h I D U A d eli vere d b y S B -3 1 8 , a n d t o preser ve he patic f u ncti o n, pre d nis o ne or e q ui vale nt 
c ortic oster oi d will be a d mi nistere d pr o p h ylacticall y starti n g 2 da ys pri or t o S B -3 1 8  i nf usi o n a n d 
will be ta pere d o v er a p eri o d of a p pr o xi matel y 2 0 wee ks (s ee A p pe n di x 3 ). 
T he  3  c o m p o ne nts of S B -3 1 8  ( Z F N 1, Z F N 2, a n d hI D U A  D o n or) will eac h b e a d de d t o 2 0 0  m L of 
di l ue nt (refer t o t he P har mac y Ma n u al)  a n d a dj uste d t o 0. 2 5 % h u ma n ser u m al b u mi n. T otal 
i nf usi o n v ol u mes will de pe n d  o n a s u bject’s c o h ort assi g n me nt a n d b o d y wei g ht . I V i nf usi o ns will 
be a d mi nistere d w hile s u bjects are i n t he h os pit al or ac ute care facilit y (refer t o t he P har m ac y 
Ma n ual).  
S u bject s will re mai n i n t he h os pital or ac ute care facilit y f or at least 2 4 h o urs after c o m pleti o n of 
S B -3 1 8  i nf usi o n f or o bser vati o n, a n d will be disc har ge d w he n all A Es a n d vital si g ns ( te mperat ure, 
heart rate , res pir at or y rate, a n d bl o o d press ur e ) are sta ble. 
After s u bjects are disc h ar ge d fr o m t he h os pital or ac ute care facilit y , st u d y visits are sc he d ule d o n 
Da y 7; Wee ks 2, 4, 6, 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, 4 8, a n d 5 2; a n d M o nt hs 1 5, 1 8, 2 1, 2 4, 
2 7, 3 0, 3 3, a n d 3 6 (see S ecti o n 6  a n d A p pe n di x 1 ). 
D uri n g t he first 2 0 w ee ks after S B -3 1 8  i nf usi o n, li ver f u ncti o n tests (as partate a mi n otra nsferase 
[ A S T], ala ni ne a mi n otra nsferas e [ A L T], t otal a n d direct bilir u bi n, al kali ne p h os p hatase, L D H, 
al b u mi n, a n d t otal pr otei n le vels) 
will be c o n d ucte d f or e val uati o n of 
A A V -m e diate d 
i m m u n o ge nicit y t wice a wee k. T he tests ma y be c o n d ucte d  re m otel y. Bl o o d sa m ples f or t hese tests 
will be dra w n 2  t o 4 da ys a part w he n p ossi ble, e xce pt f or t he first wee k w he n t he y  will be dra w n 
o n t he Da y 1 a n d D a y 7 visits . Li ver f u ncti o n tests will s u bse q ue ntl y be c o n d ucte d  at all st u d y 
visits . 
Pre vi o us  st u dies wit h I V A A V 8 FI X g e ne t h era p y ha ve  s h o w n t h at li ver tr a nsa mi nitis d ue t o A A V 
i m m u n o ge nicit y occ urs bet wee n  2 a n d 9 wee ks after i nf usi o n , a n d t hat ra pi d i nstit uti o n of 
pre d nis o ne ca n c o ntr ol t his i m m u n o ge nicit y  (Nat h wa ni et al. 2 0 1 4 ). If i n s pite of t he p retreat me nt 
wit h pre d nis o ne or e q ui vale nt c ortic oster oi d t here is e vi de nce of tra nsa mi nitis, t he d ose of 
pre d nis o ne or e q ui vale nt c ortic oster oi d  will be i ncreas e d o n a case -b y -case b asis, a n d li ver 
f u ncti o n will be ass esse d t wice a wee k u ntil n or malizati o n of li ver e nz y mes, a n d t he n p er pr ot oc ol 
t hereafter. 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 3 7  of 8 6  
4  
S U B J E C T S E L E C TI O N  
4. 1  
I ncl usi o n Criteri a 
S u bjects m ust meet all of t he f oll o wi n g criteria t o be i ncl u de d i n t he st u d y:  
1.  Si g ne d  i nf or me d c o nse nt. 
2.  > 5  y ears of a g e: 
a)  
ad ult c o h orts 1 t hr o u gh 3 : > 1 8  y ears of a ge; 
b)  
p e diatric c o h orts 4  a n d 5: 1 2 t o 1 7  years of a ge ; a n d  
c)  
p e diatric c o h orts 6  a n d 7 : 5 t o 1 1  years  of a ge . 
3.  Cli nical dia g n osis of M P S I ; I D U A defi cie nc y  c o nfir me d b y  ge ne s e q ue nci n g.  
4.  Se x uall y mat ure s u bjects m ust a gree t o use a barri er c o ntrace pti ve met h o d f or pre v e nti o n 
of A A V tra nsfer as f oll o ws: f or fe mal e s u bjects t his mea ns t hat t he s u bjects’ part n ers m ust 
use a c o n d o m fr o m d osi n g wit h S B -3 1 8 u ntil at least 3 c o nsec uti ve plas ma sa m p les after 
a d mi nistrati o n of S B -3 1 8  are n e gati ve f or A A V 2/ 6; f or male s u bjects t his mea ns t hat t he 
s u bjects m ust use a c o n d o m a n d m ust refrai n fr o m s per m d o nati o n fr o m t he ti me of S B -
3 1 8 u ntil at least 3 c o nsec uti ve se me n sa m ples aft er a d mi nistrati o n of S B -3 1 8  are n e gati ve 
f or A A V 2/ 6. A d diti o nall y, fe male p artici pa nts of c hil d-beari n g p ote ntial m ust c o nse nt t o 
use a hi g hl y effecti ve met h o d of c o ntrace pti o n . 
5.  Ma g netic res o n a nce i ma gi n g ( M RI ) n e gati ve f or li ver mass as rea d b y a ra di ol o gist . 
4. 2  
E xcl usi o n Criteri a  
S u bjects w h o meet a n y of t he f oll o wi n g criteri a will be e xcl u de d fr o m p artici pati n g i n t he st u d y: 
1.  K n o w n  t o be u nres p o nsi ve t o E R T. 
2.  Ne utralizi n g  a nti b o di es i n ser u m (i m m u ne res p o nse) t o A A V 2/ 6 .  
3.  Ser i o us i nterc urre nt ill ness or cli nicall y si g nifica nt or ga nic disease ( u nless sec o n dar y t o 
M P S I) s uc h as car di o v as c ular, he p atic, p ul m o nar y, ne ur ol o gic, or re nal disease . 
4.  Recei vi n g a nti viral t hera p y f or he patitis B or C, or wit h acti ve he patitis B ( H B V  D N A 
p ositi ve  or H B V s urface a nti g e n p ositi ve ) or h e patitis C ( H C V R N A viral l oa d) or h u ma n 
i m m u n o deficie nc y vir us ( HI V)-1/ 2 ( HI V R N A  viral l oa d  or HI V a nti b o d y p ositi ve); t o be 
c o nsi dere d n e gati ve  f or h e patitis C after treat me nt of a n acti ve H C V i nfecti o n, viral assa ys 
i n 2  sa m ples c ollecte d at least 6  m o nt hs a part m ust be ne gati ve . 
5.  Lac k of t olera nce t o E R T  wit h si g nifica nt i nf usi o n -ass ociate d reacti o ns (I A Rs) or 
occ urre nce of a n a p h yla xis.  
6.  P ol y m or p his ms i n t he Z F N -tar gete d re gi o n of t h e al b u mi n l oc us. 
7.  Li ver fi br osis sc ore of 3 or 4 o n a 0 t o 4 p oi nt scale (Des met et al. 1 9 9 4 ) if s u bject has ha d 
a li ver bi o ps y wit hi n 2 years of Scree ni n g.  
8.  Mar kers of he pati c d ysf u ncti o n as e vi de nce d b y o ne or m ore of t h e f oll o wi n g:  
a. 
Platelet c o u nt < 1 0 0 , 0 0 0/ μ L 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 3 8  of 8 6  
b.  
Al b u mi n ≤3. 2  g/ d L  
c. 
T otal bilir u bi n > 1. 5 x u p per li mit of n or mal ( U L N ) a n d direct bilir u bi n ≥0. 5  m g/ d L  
d.  
Al kali ne p h os p hatase > 2. 0 x U L N  
e. 
A L T or A S T > 2. 0 x U L N  
9.  Creati ni ne ≥ 1. 5 m g/ d L . 
1 0.  Wei g ht < 2 0 k g at Scree ni n g.   
1 1.  P re g na nt or breastfee di n g fe male. 
1 2.  C o ntrai n dicati o n t o t he use of c ortic oster oi ds.  
1 3.  C ur re nt treat me nt wit h s yste mic (I V or oral) i m m u n o m o d ulat or y a ge nt or ster oi d use 
(t o pical treat me nt all o w e d, e. g., f or ast h ma or ecze ma) . 
1 4.  Hist or y of acti ve mali g na nc y i n past 5 years ( n o n-mela n o ma s ki n ca ncer or cer vical ca ncer 
i n sit u per mitte d) . 
1 5.  Partici pati o n i n  pri or  i n vesti gati o nal dr u g or me dical de vice st u d y wit hi n t he pre vi o us 
3  m o nt hs . 
1 6.  Pri or treat m e nt wit h a ge ne t hera p y pr o d uct.  
1 7.  Hist or y of alc o h ol or s u bsta nce a b us e  t hat i n t he o pi ni o n of t he Pri nci pal I n vesti gat or ma y 
i nterfere wit h st u d y c o m plia nce. 
1 8.  Hist or y of t hera p e utic n o n -a d here nce . 
1 9.  Ele vate d or a b n or mal circ ulati n g α -fet o pr otei n (A F P ). 
2 0.  A n y ot her reas o n t hat, i n t he o pi ni o n of t he Pri nci pal I n vesti gat or or M e dical M o nit or, 
w o ul d re n der t h e s u bject u ns uita ble f or partici p ati o n i n t he st u d y . 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 3 9  of 8 6  
5  
I N F O R M E D C O N S E N T  
I nf or me d c o nse nt m ust be o btai ne d fr o m t he a d ult s u bjects or pare nts or g uar dia ns a n d asse nt m ust 
be o btai ne d fr o m pe diatric s u bjects as i nstit uti o nal p olic y all o ws bef ore a n y st u d y -relate d 
scree ni n g acti vit y is u n derta ke n t hat is n ot part of r o uti ne care. I nf or me d c o nse nt ma y be o btai ne d 
se parat el y f or Scree ni n g bl o o d tests o nl y (t o deter mi ne eli gi bilit y base d o n ne utralizi n g a nti b o dies  
t o A A V 2/ 6 a n d si n gle-n ucle oti de p ol y m or p his m [ S N P ] a nal ysis) pri or t o o btai ni n g f ull st u d y 
I nf or me d C o nse nt, if all o we d b y t he l ocal i nstit uti o nal re vie w b oar d (I R B) or i nstit uti o nal et hics 
c o m mittee ( IE C) or e q ui vale nt . T he s u bject’s le gall y a ut h orize d re prese nt ati ve ma y als o pr o vi d e 
i nf or me d c o nse nt f or s u bject partici pati o n if all o we d b y t he l ocal I R B/I E C or e q ui vale nt.  
T he Pri nci pal I n v esti gat or  or desi g nate d pers o n nel will e x plai n t o eac h s u bject or t he s u bject’s 
le gall y a ut h orize d re pres e ntati ve t he nat ur e of t h e st u d y, its p ur p ose, t he pr oce d ures, t he e x p ecte d 
d urati o n, alter nati ve t hera pies a vaila ble, a n d t he be nefits a n d ris ks of  partici pati o n. T he s u bject  or 
t he s u bject’s le g all y a ut h orize d re pres e ntati ve will recei ve a n i nf or mati o n a n d c o nse nt d oc u me nt, 
wit h t he o p p ort u nit y t o as k q uesti o ns, a n d will be i nf or me d t hat p artici pati o n is v ol u ntar y, a n d t h at 
t he s u bject ca n wit h dr a w fr o m t he st u d y at a n y ti me  wit h o ut a n y i m pact o n t he s u bject’s f ut ure 
cli nical care. T he s u bject or t he s u bject’s l e gall y a ut h orize d re prese nt ati ve will recei ve a c o p y of 
t he si g ne d a n d date d writte n i nf or me d c o nse nt f or m. Eac h s u bject will be re -c o nse nt e d at t h e ti me  
of a n y i nf or me d c o nse nt a me n d me nt, as a p plica bl e, a n d will be pr o vi de d a c o p y of t h e si g ne d a n d 
date d re vise d c o nse nt f or m. 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 4 0  of 8 6  
6  
S T U D Y M E T H O D O L O G Y  
Pri or t o i nitiati o n  of t his st u d y, t h e st u d y site s hall be a p pr o ve d b y t he I R B/ I E C or e q ui vale nt. 
S u bjects m u st be willi n g t o partici pate i n all st u d y pr oce d ures rel ate d t o t his pr ot oc ol.  
T he f oll o wi n g secti o ns descri be all st u d y pr oce d ures. A d diti o nal detaile d i nstr ucti o ns will be 
pr o vi de d  i n t he St u d y Refere n ce Ma n u al, La b orat or y Ma n ual, a n d P har m ac y Ma n ual . A  ta ble of 
all st u d y pr oce d ures is prese nte d i n t he Sc he d ule of E ve nts (see A p pe n di x 1 ).  
6. 1  
Scree ni n g  
T he o bjecti ve of S cree ni n g is t o i de ntif y s u bjects w h o meet t he state d i ncl usi o n a n d e xcl usi o n 
criteria a n d w h o are willi n g a n d a ble t o partici pate i n t he st u d y. Scree ni n g ma y ta ke u p t o 
a p pr o xi matel y 3 m o nt hs a n d ma y be perf or me d acr oss se veral visits.  
T he f oll o wi n g assess me nts a n d pr oce d ures  will be perf or me d : 
•  O btai n a si g ne d a n d date d s u bject i nf or me d c o nse nt f or m a n d a ut h orizati o n d oc u me nt t o 
use a n d discl ose me dic al i nf or mati o n pri or t o perf or mi n g a n y st u d y -s pecifi c pr oce d ures. 
•  O btai n a c o m plete me dic al hist or y.  
•  Re vie w a n d rec o r d co nc o mita nt me dicati o ns.  
•  Re vie w t he i ncl usi o n a n d e xcl usi o n criteria . 
•  C ollect de m o gra p hic i nf or mati o n.  
•  Assi g n a s u bject n u m ber . 
•  P h ysical e xa mi nati o n . 
•  Vital  si g ns. 
•  Assess me nt of A Es . 
•  E R T a d mi nistrati o n l o g.  
•  1 2 -lea d ele ctr ocar di o gra m ( E C G ). 
•  Ec h ocar di o gra m  ( E C H O). 
•  C hest x -ra y. 
•  P re g na nc y test (f or fe mal es of c hil d beari n g p ote ntial  o nl y ). 
•  Cli nical la b orat or y tests.  
•  Li ver pa nel.  
•  M P S I  ge ne s e q ue nci n g . 
•  S N P a nal ysis . 
•  Viral l oa d . 
•  Ne utralizi n g a nti b o dies t o A A V 2 / 6. 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 4 1  of 8 6  
•  G A G testi n g i n urine (c ollect sa m ples o n 3 se p arat e da ys, eac h c ollecti o n  occ urri n g  at least 
7 da ys after t he pre vi o us , a n d all c ollecti o ns occ urri n g at least 7 da ys after E R T 
a d mi nistrati o n [ +/ -1 da y]  b ut pri or t o t he ne xt E R T i nf usi o n ). 
•  I D U A / G A G t esti n g i n  bl o o d (c ollec t 7 da ys aft er E R T a d mi nistrati o n [ +/ -1 da y]).  
•  Circ ulati n g  A F P  le vel. 
•  P ul m o nar y f u ncti o n tests ( P F Ts ). 
•  V A B S -II ( Vi nel a n d A da pti ve Be ha vi or Scales) t est. 
•  Ne ur oc o g niti ve a bilities assess me nt.  
•  M RI  of li ver.  
S u bjects ma y be re -s cree ne d f or partici pati o n i n t he st u d y i n t he j u d ge me nt of t he Pri n ci pal 
I n v esti gat or a n d after c o ns ultati o n wit h Sa n ga m o. F or re -scree ni n g, t he f oll o wi n g assess me nts 
perf or me d i n t he pre vi o us 6 m o nt hs ma y be us e d f or e v al uati o n of i ncl usi o n/e xcl usi o n criteria at 
t he j u d ge me nt of t he Pri n ci pal I n vesti gat or: 
•  E C H O . 
•  C hest X -Ra y . 
•  P F Ts .  
•  M RI of li ver a n d/ or brai n a n d cer vi cal s pi ne . 
F urt her, g e netic mar ker a nal ysis i ncl u di n g S N P a nal ysis a n d M P S I se q ue nci n g will  n ot be 
re peat e d as res ults of t hese assess me nts d o n ot c ha n ge o ver ti me . 
6. 2  
S u bject E nr oll me nt  
Bef ore a s u bject is assi g n e d t o a d ose c o h ort, t he st u d y site pers o n nel m ust verif y t hat t h e s u bject 
f ulfills all eli gi bilit y criteria . 
T he pe diatric c o h orts will be e nr olle d o nl y after re vie w of c u m ulati ve a d ult safet y data b y a n 
i n de pe n de nt, e xter nal S M C (see Secti o n 1 2. 3 ). 
6. 3  
B aseli ne  
Baseli ne assess me nts will be perf or m e d  wit hi n  2 1 da ys pri or t o S B -3 1 8 i nf usi o n .  
I n s u bjects recei vi n g E R T, E R T s hall be wit h hel d d uri n g t he wee k of t he a d mi nistrati o n of S B -3 1 8  
t o e na ble acc urate baseli ne testi n g   
T he f oll o wi n g assess me nts a n d pr oce d ures  will be  perf or me d : 
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns . 
•  P h ysical e xa mi nati o n . 
•  Vital  si g ns. 
•  Assess me nt of A Es . 
•  E R T a d mi nistrati o n l o g.  
•  J oi nt ra n ge of m oti o n (JR O M ). 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 4 2  of 8 6  
•  Ne ur ol o gic cra nial ner ve e xa m a n d m uscle stre n gt h t esti n g of t he u p per e xtre mities.  
•  1 2 -lea d E C G. 
•  P re g na nc y test (f or fe mal es of c hil d beari n g p ote ntial  o nl y ). 
•  Cli nical la b orat or y tests.  
•  Li ver pa nel.  
•  C hi meris m assa y (f or p ost -H S C T s u bjects o nl y).  
•  G A G  testi n g i n uri ne. 
•  I D U A / G A G t esti n g i n bl o o d. 
•  Vect or ge n o m e  P C R i n plas ma, sali va, uri ne, st o ol, a n d se me n ( mal es o nl y). 
•  P F Ts . 
•  6 -mi n ute wal k test ( 6 M W T ). 
•  Vis ual ac uit y test  a n d cor neal cl o u di n g e xa m . 
•  Ne ur oc o g niti ve a bilities tests b y W A SI -II ( Wec hsler A b bre viate d Scale of I ntelli ge nce), 
W P P SI -I V (Wec hsler Presc h o ol a n d Pri mar y Scale of I ntelli ge nce ), or B SI D-III (B a yle y 
Scales of I nfa nt De v el o p me nt ), a n d b y V A B S-II. 
•  M RI of brai n a n d cer vical s pi ne.  
•  A dr e n oc ortic otr o pic h or m o ne ( A C T H ) sti m ulati o n (c os y ntr o pi n) test ( pri or t o pre d nis o ne 
or e q ui vale nt c ortic oster oi d ). 
•  Li ver bi o ps y.  
•  L u m bar p u nct ure.  
•  I m m u n o ge nicit y ass a ys. 
•  P re d nis o ne or e q ui vale nt c ortic oster oi d  a d mi nistrati o n  (starti n g 2 da ys bef ore S B -3 1 8 
i nf usi o n). 
6. 4  
D a y 0 (S B -3 1 8 I nf usi o n ) 
S u bject s will recei ve t he S B-3 1 8 i nf usi o n at a h os pital or ac ute care facilit y , re mai n t here f or at 
least 2 4 h o urs  aft er t he i nf usi o n  f or o bser vati o n, a n d be  disc har ge d w he n all A Es a n d vital si g n s 
are sta ble.  
T he f oll o wi n g assess me nts a n d pr oce d ures  will be perf or m e d: 
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns . 
•  P h ysical e xa mi nati o n . 
•  Vital  si g ns (f or fre q ue nc y, refer t o t he St u d y Refere nce M a n ual ). 
•  Assess me nt of A Es . 
•  E R T a d mi nistrati o n l o g.  

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 4 3  of 8 6  
•  Pre g na nc y test ( fe mal es of c hil d beari n g p ot e ntial, o nl y  if > 7 da ys fr o m Baseli ne  pre g na n c y 
testi n g). 
•  Pre d nis o ne or e q ui vale nt c ortic oster oi d  ad mi nistrati o n . 
•  I nf usi o n of S B -3 1 8  via a peri p heral vei n cat het er . 
6. 5  
D a y 1  
All s u bjects will re mai n i n t he  h os pital or  ac ute care facilit y  f or at least 2 4 h o urs  after c o m pleti o n 
of S B -3 1 8  i nf usi o n. S u bjects will be disc har ge d w he n  all A Es  a n d vital si g ns  are sta ble.  
T he f oll o wi n g assess me nts a n d pr oce d ures  will be perf or me d:  
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns . 
•  P h ysical e xa mi nati o n . 
•  Vital si g ns (c o nti n ue d meas ure m e nt fr o m Da y 0 ). 
•  Assess me nt of A Es . 
•  C li nical la b orat or y tests. 
•  Li ver pa nel.  
•  Vect or ge n o m e P C R i n plas ma ( 1 2 h o urs after e n d of S B-3 1 8 i nf usi o n) . 
•  P re d nis o ne or e q ui vale nt c ortic oster oi d  a d mi nistrati o n . 
6. 6  
D a y 7 ( +/- 1 d a y)  
T he f oll o wi n g assess me nts a n d pr oce d ures will be perf or me d : 
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns . 
•  P h ysical e xa mi nati o n . 
•  Vital  si g ns. 
•  Assess me nt of A Es . 
•  E R T a d mi nistrati o n l o g.  
•  1 2 -lea d E C G. 
•  Li ver pa nel.  
•  Vect or ge n o m e P C R i n plas ma, sali va, uri ne, st o ol, a n d se me n ( mal es o nl y). 
•  P re d nis o ne or e q ui vale nt c ortic oster oi d  ad mi nistrati o n . 
6 . 7 
Wee ks 2, 4, 6,  a n d 8  ( +/- 2  d a y s) 
T he f oll o wi n g assess me nts a n d pr oce d ures will be  perf or me d  u nl ess ot her wise  sti p ulate d:  
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns . 
•  P h ysical e xa mi nati o n . 
•  Vital  si g ns. 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 4 4  of 8 6  
•  Assess me nt of A Es . 
•  E R T a d mi nistrati o n l o g.  
•  Pre g na nc y test (fe males of c hil d beari n g p ote nt ial o nl y; at Wee ks 4 a n d 8 o nl y). 
•  Cli nical la b orat or y tests. 
•  Li ver pa nel  (t wi ce w ee kl y; ma y be c o n d ucte d re m otel y). 
•  G A G testi n g i n uri ne.  
•  I DU A  / G A G t esti n g i n bl o o d.  
•  Circ ulati n g A F P le vel  (at Wee ks 4 a n d 8  o nl y ). 
•  V ect or g e n o me P C R i n plas ma, sali va, uri ne, st o ol, a n d se me n ( males o nl y; at Wee ks 2, 4, 
a n d 8  o nl y ). 
•  Im m u n o ge nicit y  ass a ys (at Wee k 4 o nl y). 
•  P re d nis o ne or e q ui vale nt c ortic oster oi d  a d mi nistrati o n . 
6. 8  
Wee ks 1 2, 1 6, 2 0 , 2 4 , 2 8, 3 2, 3 6, 4 0, 4 4, 4 8 , a n d 5 2 ( +/- 1 wee k)  
T he f oll o wi n g assess me nts a n d pr oce d ures will be  perf or me d u nl ess ot her wise  sti p ulate d:  
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns . 
•  P h ysical e xa mi nati o n  (at Wee ks 1 2, 1 6, 2 0, 2 4, 3 6, a n d 4 8 o nl y) . 
•  Vital  si g ns (at Wee ks 1 2, 1 6, 2 0, 2 4, 3 6, a n d 4 8 o nl y). 
•  Assess me nt of A Es.  
•  E R T a d mi nistrati o n l o g.  
•  JR O M  (at Wee ks 2 4 a n d 4 8 o nl y). 
•  Ne ur ol o gic cra nial ner ve e xa m a n d m uscle stre n gt h testi n g of t he u p per e xtre mities (at 
Wee ks 2 4  a n d 4 8  o nl y ). 
•  1 2 -lea d E C G (at Wee ks 2 4 an d 4 8 o nl y ). 
•  E C H O  (at Wee k 4 8 o nl y ). 
•  Pre g na nc y test (fe males of c hil d beari n g p ote ntial o nl y; at Wee ks 1 2, 1 6, 2 0, 2 4, 3 6, a n d 4 8 
o nl y).  
•  Cli nical la b orat or y tests (at Wee ks 1 2, 1 6, 2 0, 2 4, 3 6, a n d 4 8 o nl y). 
•  Li ver pa n el ( t wic e wee kl y u ntil Wee k 2 0; t h e n at Wee ks 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, 4 8, a n d  5 2 ; 
ma y  be c o n d uct e d re m ot el y u ntil Wee k 2 0 a n d at Wee ks 2 8, 3 2, 4 0, 4 4, a n d 5 2 ). 
•  C hi meris m assa y (at Wee ks 1 2 a n d 4 8 o nl y; f or p ost -H S C T s u bjects o nl y)  
•  G A G  testi n g i n uri ne. 
•  I D U A / G A G t esti n g i n bl o o d (at Wee ks 1 2, 1 6, 2 0, 2 4, 3 6, a n d 4 8 o nl y).  
•  Circ ulati n g A F P le vel (at Wee ks 1 2, 2 4 , a n d 4 8  o nl y ). 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 4 5  of 8 6  
•  Vect or ge n o m e  P C R i n plas ma, sali va, uri ne, st o ol, a n d se me n ( males o nl y) (at Wee ks 1 2, 
1 6, 2 0, 2 4, 3 6, a n d 4 8 o nl y).  
•  P F Ts  (at W ee ks 2 4  a n d 4 8 o nl y ). 
•  6 M W T  (at W ee ks 2 4  a n d 4 8 o nl y ). 
•  Vis ual ac uit y test  a n d cor neal cl o u di n g e xa m  (at Wee ks 2 4 a n d 4 8  o nl y ). 
•  Ne ur oc o g niti ve a bilities tests b y W A SI -II, W P P SI -I V, or B SI D-III, a n d b y V A B S-II (at 
Wee ks 2 4 a n d 4 8 o nl y) . 
•  M RI of li ver (at W ee ks 2 4 a n d 4 8  o nl y ). 
•  M RI of brai n a n d cer vical s pi ne (at Wee k 4 8 o nl y).  
•  A C T H sti m ulati o n (c os y ntr o pi n) test (at 
Wee k 2 0 o nl y or at e n d of pre d nis o ne  or 
e q ui vale nt c ortic oster oi d  ta per; see A p pe n di x 3 ). 
•  Li ver bi o ps y  (at W ee ks 2 4 a n d 4 8 o nl y). 
•  L u m bar p u nct ure (at W ee ks 2 4 a n d 4 8 o nl y).  
•  Im m u n o ge nicit y ass a ys (at Wee ks 1 2, 2 4, 3 6, a n d 4 8 o nl y). 
•  P re d nis o ne or e q ui vale nt c ortic oster oi d  a d mi nistrati o n (t hr o u g h Wee k 2 0 o nl y). 
6. 9  
M o nt hs 1 5, 1 8, 2 1, 2 4, 2 7, 3 0, 3 3 , a n d 3 6 / En d of St u d y  ( +/-1 m o nt h)  
S u bjects will be e val uate d e ver y 3 mo nt hs i n Y ear s 2 a n d 3  after  S B -3 1 8  i nf usi o n.  
A n E n d of St u d y ( E O S ) visit will be c o n d ucte d at  M o nt h 3 6 .  
At t he E O S  visit , s u bjects will be as ke d t o partici pate i n  t he LT F U  St u d y.  St u d y s u bjects ma y 
partici pate i n t h e L T F U St u d y after 1 2 m o nt hs of f oll o w -u p i n t h is st u d y, i n w hic h case a n E O S 
visit ma y be c o n d ucte d a n yti me after Wee k 5 2 b ut bef ore t he ne xt s c he d ule d st u d y visit . St u d y 
partici pa nts w h o wis h t o e nr oll i n t he L T F U St u d y wit h less t ha n 1 2 m o nt hs of f oll o w -u p i n t his 
pri mar y st u d y  ma y be c o nsi dere d o n a case -b y -case b asis at t he j u d ge me nt of t he Pri nci pal 
I n v esti gat or a n d aft er c o ns ultati o n wit h t he S p o ns or. I n t h ese cases a n E O S visit ma y be c o n d u cte d 
a n yti me w he n tra nsiti o n t o t he L T F U st u d y is i m mi ne nt . I nf or me d c o nse nt will be o btai ne d prior 
t o partici pati n g i n t he LT F U  St u d y.   
T he  f oll o wi n g assess me nts a n d pr oce d ures will be  perf or me d u nl ess ot her wise  sti p ulate d: 
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns . 
•  P h ysical e xa m i nati o n. 
•  Vital si g ns.  
•  Assess me nt of A Es . 
•  E R T a d mi nistrati o n l o g.  
•  JR O M  (at M o nt hs 1 8, 2 4, 3 0, a n d 3 6/ E O S o nl y) . 
•  Ne ur ol o gic cra nial ner ve e xa m a n d m uscle stre n gt h testi n g of t he u p per e xtre mities  (at 
M o nt hs 1 8, 2 4, 3 0, a n d 3 6 / E O S o nl y ). 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 4 6  of 8 6  
•  1 2 -lea d E C G (at M o nt hs 1 8, 2 4, 3 0, a n d 3 6/ E O S o nl y) . 
•  E C H O  (at M o nt hs 2 4 a n d 3 6 / E O S o nl y ). 
•  Cli nical la b orat or y tests. 
•  Li ver pa nel.  
•  C hi meris m assa y (at M o nt h 3 6 / E O S o nl y; f or p ost-H S C T s u bjects o nl y)  
•  G A G  testi n g i n uri ne. 
•  I D U A / G A G t esti n g i n bl o o d.  
•  Circ ulati n g  A F P le vel (at M o nt hs 1 8, 2 4, 3 0, a n d 3 6 / E O S o nl y ). 
•  P F Ts (at M o nt hs 1 8, 2 4, 3 0, a n d 3 6 / E O S o nl y ). 
•  6 M W T  (at M o nt hs 1 8, 2 4, 3 0, a n d 3 6/ E O S o nl y ). 
•  Vis ual ac uit y test  a n d cor ne al cl o u di n g e xa m ( at M o nt hs 2 4  a n d 3 6/ E O S o nl y ). 
•  Ne ur oc o g niti ve a bilities tests b y W A SI -II, W P P SI -I V, or B SI D-III, a n d b y V A B S-II (at 
M o nt hs 1 8, 2 4, 3 0, a n d 3 6 / E O S o nl y) . 
•  M RI of li ver (at M o nt hs 1 8, 2 4 , 3 0 a n d 3 6 / E O S o nl y ). 
•  M RI of brai n a n d cer vical s pi ne (at M o nt hs 2 4 a n d 3 6 / E O S o nl y).  
•  Im m u n o ge nicit y ass a ys (at M o nt hs 1 8 a n d 2 4 o nl y). 
6. 1 0  
E arl y Ter mi n ati o n  
S u bjects  w h o disc o nti n u e fr o m t he st u d y pre mat urel y or are wit h dr a w n  fr o m t he st u d y will be 
as ke d t o ret ur n t o t he st u d y site f or  a n Earl y T er mi nati o n  v isit ( E T V).  
It is at t he discreti o n of t he Pri nci pal I n vesti gat or , i n c o ns ultati o n wit h t he Me dical M o nit or, t o 
wai ve a n y pr oce d ure if t h e pr oce d ure  has bee n perf or me d wit hi n t he sta n dar d i nter val of sc he d ule d 
st u d y visits per pr ot oc ol.  
T he f oll o wi n g assess me nts a n d pr oce d u res will be perf or me d : 
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns . 
•  P h ysical e xa m . 
•  Vital  si g ns. 
•  Assess me nt of A Es . 
•  E R T a d mi nistrati o n l o g.  
•  JR O M.  
•  Ne ur ol o gic cra nial ner ve e xa m a n d m uscle stre n gt h testi n g of t he u p per e xtre mities . 
•  1 2 -lea d E C G. 
•  E C H O.  
•  Cli nical la b orat or y tests. 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 4 7  of 8 6  
•  Li ver pa nel.  
•  C hi meris m assa y.  
•  G A G  testi n g i n uri ne. 
•  I D U A / G A G t esti n g i n bl o o d.  
•  Circ ulati n g  A F P le vel . 
•  P F Ts . 
•  6 M W T . 
•  Vis ual ac uit y test a n d c or neal cl o u di n g e xa m . 
•  Ne ur oc o g niti ve a bilities tests b y W A SI -II, W P P SI -I V, or B SI D-III, a n d b y V A B S -II. 
•  M RI of li ver.  
•  M RI of brai n a n d cer vical s pi ne.  
6. 1 1  
E R T Wit h dr a w al ( a n y ti me after Wee k 1 2)  
S u bjects w h o are willi n g a n d  w h o are at least 1 2 wee ks p ost a d mi nistrati o n of S B -3 1 8 ma y be 
c o nsi dere d f or wit h dr a wal of E R T b y t he Pri nci pal I n v esti gat or after c o ns ultati o n wit h t he 
S p o ns or. If u n der g oi n g E R T wit h dra wal, s u bjects m ust be me dicall y sta ble a n d a gree t o i ncrease d 
safet y m o nit ori n g a n d la borat or y  testi n g u ntil t he E R T W it h dra wal F oll o w -U p visit.  
T he E R T Wit h dra w al visit ma y occ ur c o n c urre ntl y or i n de pe n de nt of a re g ular sc he d ule d visit .  
T he E R T Wit h dra wal visit s h o ul d be c o m bi ne d wit h a re g ular sc h e d ule d visit w he ne ver p ossi ble 
t o re d uce st u d y b ur de n.  
T he f oll o wi n g assess me nts a n d pr oce d u res will be perf or me d: 
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns.  
•  P h ysical e xa mi nati o n.  
•  Vital  si g ns. 
•  Assess me nt of A Es.  
•  E R T a d mi nistrati o n l o g.  
•  Cli nical la b orat or y tests.  
•  Li ver pa nel.  
•  G A G  testi n g i n uri ne. 
•  I D U A / G A G t esti n g i n bl o o d. 
•  P F Ts.  
•  6 M W T.  

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 4 8  of 8 6  
6. 1 2  
E R T Wit h dr a w al M o nit ori n g ( E R T Wit h dr a w al Wee ks 1, 2, 3, 4, 6, 8, 1 0, a n d 1 2 [ +/- 
2 d a ys])  
E R T Wit h dra wal M o nit ori n g visits will ta ke place o n a wee kl y basis f or t he first 4 wee ks, a n d o n 
a bi wee kl y basis f or t he last 8 wee ks f oll o wi n g t he E R T Wit h dra wal visit u ntil t he E R T Wit h dra wal 
F oll o w -U p visit.  
E R T Wit h dra w al M o nit ori n g visits s h o ul d be c o m bi ne d wit h re g ular sc h e d ule d visits w he n e ver 
p ossi ble t o re d uce st u d y b ur de n , a n d ma y be c o n d ucte d re m ote l y.  
T he f oll o wi n g assess me nts a n d pr oce d u res will be perf or me d: 
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns.  
•  Assess me nt of A Es.  
•  E R T a d mi nistrati o n l o g.  
•  Li ver pa nel.  
•  G A G  testi n g i n uri ne. 
•  I D U A / G A G t esti n g i n bl o o d. 
6. 1 3  E R T Wit h dr a w al F oll o w -U p ( u p t o 1 2  wee ks p ost -E R T  Wit h dr a w al  visit ) 
T he E R T 
Wit h dra w al F oll o w -U p visit ca n occ ur at a n y ti me u p t o 1 2  wee ks after t he E R T 
Wit h dra wal visit at t he discr eti o n of t he Pri nci pal I n vesti gat or. 
T he f oll o wi n g assess me nts a n d pr oce d u res will be perf or me d: 
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns.  
•  P h ysical e xa mi nati o n.  
•  Vital  si g ns. 
•  Assess me nt of A Es.  
•  E R T a d mi nistrati o n l o g.  
•  Cli nical la b orat or y tests.  
•  Li ver pa nel.  
•  G A G  testi n g i n uri ne. 
•  I D U A / G A G t esti n g i n bl o o d. 
•  P F Ts.  
•  6 M W T.  
•  E R T cli nical assess me nt . 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 4 9  of 8 6  
7  
I N V E S TI G A TI O N A L P R O D U C T A N D O T H E R S T U D Y M E DI C A TI O N S  
7 . 1 
S B -3 1 8  
S B -3 1 8 is a c o m bi nati o n of 3  rec o m bi na nt a d e n o-associate d vir us s er ot y pe 2/ 6 (r A A V 2/ 6) vect ors 
t hat e nc o de: 
•  Z F N 1  ( S B-4 7 1 7 1 ): Left -si de Z F N t hat tar g ets b ase p airs 4 4 7 -4 6 1 of t he al b u mi n l oc us  
relati ve t o t he tra nscri pti o n i nitiati o n site (Z F N 1 pr o d uct vials are la bele d as 
S B -A 6 P -Z L E F T ). 
•  Z F N 2  ( S B-4 7 8 9 8 ): Ri g ht -si de Z F N  t hat tar g ets base pairs 4 6 8 -4 8 5 of t he al b u mi n l oc us 
relati ve t o t he tra nscri pti o n i nitiati o n site  (Z F N 2 pr o d uct vials are la bele d as 
S B -A 6 P -Z RI G H T ). 
•  h I D U A D o n or  ( S B-I D U A): D N A re pair te m plat e t hat e nc o des  a pr o m ot o rless h u ma n 
i d ur o ni dase ( hI D U A) tra ns ge ne (hI D U A 
D o n or  pr o d uct 
vials are la bele d as 
S B -A 6 P -H R L ). 
P urifie d l ots of rec o m bi na nt vect or are f or m ulate d i n p h os p hate b uffere d sali ne ( P B S) c o ntai ni n g 
Ca Cl 2, M g Cl2, Na Cl , S ucr ose  & K olli p h or ( P ol o xa mer) P 1 8 8 a n d fille d at v ol u mes of eit her 5  m L  
or 1 0  m L  i nt o vials, w hi c h are t he n st ore d at ≤-6 5° C . T h e l ots are teste d f or i de ntit y, sterilit y, 
p ote nc y, a n d sta bilit y.  
7 . 1. 1  I n ve nt or y, St or a ge, a n d H a n dli n g of t he Dr u g Pr o d uct 
T he S B -3 1 8 c o m p o ne nts  re q uire d f or s u bject treat me nt will be s hi p pe d t o t he st u d y ce nter wit h 
dr y ice a n d te m perat ur e m o nit ori n g de vice , a n d m ust  be st ore d at ≤ -6 5 oC  ( wit h te m perat ure 
m o nit ori n g) pri or t o a d mi nistrati o n.  
A  C li nical C ertificat e of A nal ysis  f or eac h S B-3 1 8 c o m p o ne nt  will acc o m pa n y eac h s hi p me nt. T h e 
vials will ha ve a la b el affi xe d c o ntai ni n g t h e f oll o wi n g i nf or mati o n : vect or i de ntit y, l ot n u m ber, 
c o nce ntr ati o n, v ol u me, st ora ge c o n diti o n s, ma n ufact ur er, dat e of ma n ufact uri n g , s p o ns or, a n d 
“Ca uti o n: F or in vesti ga ti o nal u se o nl y ”.  
S hi p me nts will c o nsist of s u bject -s p ecific kits t hat c o m prise t h e 3  S B -3 1 8 c o m p o ne nts i n t he 
q ua ntities re q uire d base d o n t he s u bject’s wei g ht a n d c o h ort . Kit la b els will c o ntai n t he f oll o wi n g 
a d diti o nal i nf or mati o n: s u bject I D n u m ber, pr ot oc ol n u m ber , a n d q ua ntit y.  
T he st u d y ce nter is re q uir e d t o mai ntai n c o m plete rec or ds of all st u d y pr o d ucts recei ve d d uri n g t he 
c o urse of t his st u d y, as well as of la bele d pr o d uct t hat is dis pe nse d. At t he c o ncl usi o n or 
ter mi nati o n of t his st u d y, ret ur n or destr ucti o n of all dr u g s u p plies m ust be c o or di nate d wit h 
Sa n ga m o  (refer t o t he P h ar mac y M a n ual  f or a d diti o nal details). 
T he Pri nci pal I n v esti gat or a grees n ot t o s u p pl y  la bele d pr o d uct t o a n y p ers o n ot her t ha n st u d y 
pers o n nel a n d s u bjects i n t h is st u d y. 
7 . 1. 2 S B -3 1 8  A d mi nistr ati o n  
S B -3 1 8  will be s hi p pe d t o t he st u d y site pri or t o t he sc he d ule d i nf usi o n. O n Da y 0 , aft er t he s u bject 
has arri v e d at t he h os pital or ac ute care facilit y  a n d has bee n c o nfir me d t o be eli gi ble f or i nf usi o n , 
the  3  c o m p o ne nts  of S B -3 1 8  ( Z F N 1, Z F N 2, a n d h I D U A D o n or ) will be t ha we d  b y placi n g t he 
vials at r o o m te m perat ure . T he n eac h c o m p o ne nt will be a d de d t o  2 0 0  m L  of dil ue nt (refer t o t he 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 5 0  of 8 6  
P har mac y Ma n u al ) a n d a dj uste d t o 0. 2 5 % h u ma n ser u m al b u mi n.  T otal i nf usi o n v ol u mes will be 
calc ulate d acc or di n g t o t he s u bject’s c o h ort assi g n me nt a n d b o d y wei g ht ( k g).  
O nce t he S B -3 1 8 i nf usi o n  is pre pare d it s h o ul d be tra ns p orte d at r o o m te m perat ur e t o t he i nf usi o n 
facilit y at t he h os pital or ac ute care facilit y, a n d be ke pt at r o o m te m perat ure pri or t o i nf usi o n. S B -
3 1 8 will be i nf use d w hile m o nit ori n g t he s u bject’s vital si g ns  (te m perat ure, heart rate , res pirat or y 
rate, a n d bl o o d press ur e ) pre -, d uri n g, a n d p ost-i nf usi o n (f or fre q ue n c y, refer t o t he St u d y 
Refere n ce  M a n ual ) u ntil disc har ge. 
F or d etaile d i nstr ucti o ns f or t ha wi n g a n d i nf usi n g S B -3 1 8 , refer t o t he P har mac y Ma n ual . 
Si de effects f oll o wi n g S B -3 1 8 i nf usi o ns ma y i ncl u de tra nsie nt fe v er, c hills, a n d/ or na usea. T hese 
s y m pt o ms ca n be treate d  wit h aceta mi n o p he n ( T yle n ol or Paraceta m ol) 6 5 0 m g b y m o ut h a n d 
di p he n h y dra mi ne h y dr oc hl ori de ( Be na dr yl) 2 5 -5 0 m g b y m o ut h or I V  or e q ui vale nt me dicati o n . 
T hese me dicati o ns ma y be re peate d e v er y 3 -4 h o urs as nee de d.  
7 . 1. 3 Prec a uti o ns  
S B -3 1 8  is a n i n vesti gati o nal pr o d uct, a n d t here is a p ote ntial  ris k of se vere h y p erse nsiti vit y 
reacti o n (e. g., a na p h yla xis ). E mer ge nc y m e dical e q ui p me nt m ust  be a vaila ble d uri n g t he i nf usi o n 
i n case t he su bject has a n aller gic res p o nse,  sev ere h y p ote nsi ve crisis, or a n y ot her reacti o n t o t he 
i nf usi o n. Vital si g ns (te m perat ure, heart rate , res pirat or y rat e, a n d bl o o d press ure) m ust  be ta ke n 
bef ore , d uri n g, a n d aft er i nf usi o n  (see A p pe n di x 1  a n d refer t o t he St u d y Refere n ce Ma n ual ). I n 
t he u nli kel y e ve nt t hat t he s u bject de v el o ps se psis or s yste mic bactere mia f oll o wi n g S B -3 1 8 
i nf usi on, a p pr o priate c ult ures a n d me dical ma na g e me nt s h o ul d be i nitiate d.  
All da n ger o us  g o o ds mat erials, i ncl u di n g dia g n ostic s peci me ns a n d i nf ecti o us s u bsta nces, m ust be 
tra ns p orte d acc or di n g t o t he i nstr ucti o ns detaile d i n t he I nter nati o nal Air Tra ns p ort Ass o ciati o n 
(I A T A) Da n ger o us G o o ds Re g ulati o ns. 
7 . 1. 4 D ose M o dific ati o ns  
N o d ose m o dif icati o ns are p ossi ble wit hi n a n i n di vi d ual s u bject si nce t his is a si n gle i nf usi o n st u d y. 
7 . 2 
C o nc o mit a nt Me dic ati o n  a n d S u p p orti ve C are  
T he Pri nci pal I n v esti gat or  will rec or d all c o nc o mita nt me dicati o ns , i ncl u di n g o ver -t he-c o u nt er 
me dici nal pr o d ucts, dietar y s u p ple me nts, her bal me dicati o ns , a n d me dicati o ns gi ve n i n treat me nt 
of A Es, ta k e n b y a s u bject fr o m Scree ni n g t hr o u g h o ut t he c o urse of t h e st u d y  o n t he c o n c o mita nt 
me dicati o ns pa ge i n t he s u bject’s cas e re p ort  f or m ( C R F). 
S u bjects  w h o recei ve d E R T  pri or t o st u d y e nr oll me nt s h o ul d c o nti n ue t o recei v e E R T d uri n g t he 
st u d y as per st a n dar d of care  u nless t he y u n der g o pr ot oc ol s pecifie d  E R T wit h dra wal (see  
Secti o n  1 1. 4 ), e xce pt d uri n g t he wee k  of t he S B -3 1 8 i nf usi o n, a n d s uc h treat me nt s h o ul d be 
rec or de d o n t he c o n c o mita nt me dicati o ns pa ge. 
T reat me nt wit h pre d nis o ne  or e q ui vale nt c ortic oster oi d  a n d pre-treat me nt wit h aceta mi n o p he n  
(T yle n ol or P araceta m ol) a n d di p he n h y dra mi ne h y dr oc hl ori de or e q ui val e nt me dicati o n s h o ul d 
als o be rec or de d o n t he c o nc o mita nt me dicati o ns pa ge. 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 5 1  of 8 6  
8  
S A F E T Y A N D P O T E N TI A L RI S K S  
8 . 1 
S B -3 1 8  
T he 3  i n di vi d ual r A A V v ect ors e nc o di n g t he i n di vi d ual al b u mi n Z F Ns a n d t he h I D U A D o n or  are 
pac ka g e d as A A V ser ot y pe 2/ 6 ma de i n a Bac ul o vir us e x pressi o n s yste m. T hese r A A V vect ors are 
n o n -re plicati n g, a n d effi cie ntl y tra ns d uce n o n -di vi di n g cells s uc h as li ver he pat o c ytes. rA A V 
vect ors d o n ot acti vel y i nte grate i nt o t he h ost cell ge n o me a n d d o n ot e n c o de a n y viral pr otei ns. 
T he S B -3 1 8 r A A V 2/ 6 v ect ors are pse u d ot y pe d v ect ors wit h b ot h i n verte d t er mi nal re p eats (I T Rs) 
bei n g deri ve d fr o m A A V 2 I T Rs , a n d t he vir us is p ac ka g e d i n t he pres e nce of t he A A V 2 re p ge n e  
a n d A A V 6 ca p g e ne. Tiss ue  tr o pis m of t hese pse u d ot y pe d vect ors is c o m pletel y de p e n de nt o n t he 
pr o perties of t he ca psi d pr otei ns e nc o d e d b y t he A A V 6 ca p ge n e.  T he A A V 2/ 6 ser ot y pe was 
c h ose n base d o n pil ot st u dies i n vitr o a nd i n viv o i n mice t hat de m o nstrate d t hat r A A V 2/ 6 
effecti vel y deli vere d t he hI D U A tra ns g e ne cassett e t o li ver he pat oc ytes, res ulti n g i n e x pressi o n of 
hI D U A i n t he s yste mic circ ulati o n . 
As of 1 1 Se pte m ber 2 0 1 8, o ne s u bject wit h 
M P S I has recei ve d S B -3 1 8 at a  d ose of 
1. 0 0 E + 1 3  v g/ k g. T he s u bject t olerate d t he i nf usi o n well a n d re p orte d n o a d verse e ve nts as of 
7  wee ks p ost i nf usi o n. . 
A si milar Z F N -me diate d 
i n viv o ge n o me e diti n g P hase I st u d y f or 
M P S II is o n g oi n g 
( S B-9 1 3 -1 6 0 2).  T he st u d y treat me nt, S B -9 1 3, is a r A A V 2/ 6 -b ase d ge ne tra nsfer a ge nt t hat 
c o m prises t he i de ntical Z F N c o m p o ne nts as S B -3 1 8 ( na mel y, S B -4 7 1 7 1 a n d S B -4 7 8 9 8) b ut differs 
fr o m S B-3 1 8 i n t he d o n or c D N A ( w hic h i n S B-9 1 3 e nc o des h u ma n i d ur o n ate -2 -s ulf atase). As of 
1 1 Se pte m ber 2 0 1 8, 6 s u bjects wit h M P S II h a v e recei ve d S B -9 1 3 at d oses of u p t o 5. 0 0 E + 1 3 
v g/ k g. S B -9 1 3 was w ell t olerate d, a n d re p orte d A Es were m ostl y mil d ( Gra de 1) i n se v erit y a n d 
u nre late d t o t he st u d y treat me nt. N o S A Es relate d t o S B -9 1 3 were re p orte d. ( F or f urt her d etails, 
see Secti o n 1. 4 ). 
T he i m m u ne s yste m of s u bjects i n t his st u d y ma y be e x p ose d t o a nti ge ns  arisi n g fr o m t he f orei g n 
A A V ca psi d pr otei n, t he  e n d o ge n o us hI D U A , a n d t he e n gi neere d Z F Ns. Cli nical st u dies t o date 
s u g gest a n i m m u ne res p o nse will be ge nerate d t o A A V ca psi d pr otei n, b ut w het her a n i m m u ne 
res p o nse will de vel o p a gai nst hI D U A re mai ns t o be deter mi ne d. I n t he re gistrati o n st u dies f or 
Al d uraz y me, 9 9 of 1 0 2 patie nts ( 9 7 %) de v el o pe d I g G a nti b o dies t o  α -L -i d ur o ni dase. H o we ver, 
Al d uraz y me is a p ol y m or p hic varia nt of hI D U A t h at is pr o d uce d i n C hi nese Ha mster O var y cells. 
It is u n k n ow n w het her  a nti b o dies will als o de vel o p a gai nst a pr otei n  wit h a gl yc os yl ati o n patter n 
deri ve d fr o m h u ma n he pat oc yte pr o d ucti o n of t he pr otei n . F ort u natel y, a nti b o d y le vels d o n ot 
affect t he t hera p e utic efficac y ( 6 M W T a n d P F Ts ) of Al d uraz y me. Z F Ps are u bi q uit o us as t he 
D N A -bi n di n g d o mai ns of tra nscri pti o n fact ors i n h u ma n cells, s o ma y ha v e li mite d i m m u n o ge nic 
p ote ntial; i n c o ntrast , t he F ok I n ucleas e d o mai n of t he Z F N is of bacteri al ori gi n. I n e xte nsi ve 
e val uati o ns i n n o n -h u ma n pri mates, n o c o nsiste nt e vi de nce f or h u m oral or cell -me diate d a d a pti ve 
i m m u ne res p o nses t o e n gi neere d Z F N c o m p o ne nts has bee n f o u n d.  
Alt h o u g h A A V is a re plicati o n defecti ve vir us, h u ma ns are nat urall y i nfecte d d uri n g c hil d h o o d , 
pr o ba bl y i n c o nj u ncti o n wit h a hel per vir us i nf ecti o n s uc h as a de n o vi r us. T heref ore, pretreat me nt  
n e utralizi n g a nti b o d ies t o A A V will affect tra ns d ucti o n b y f or mi n g i m m u ne c o m ple xes wit h t he 
i nf use d vect or a n d t here b y pre ve nt h e pat oc yte tra ns d ucti o n. F urt her m ore, f oll o wi n g  tra ns d ucti o n, 
me m or y C D 8 T cells ma y be reacti vate d a n d eli mi nate tra ns d uce d he p at oc ytes t hat e x pre ss A A V 
pr otei n -deri ve d e pit o pes . As des cri be d earlier, r es ults fr o m cli nical  st u dies s u g gest t hat 

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i m m u n os u p pressi o n, f or e xa m ple wit h c ortic ost er oi ds, ma y be necessar y t o ac hie ve s ustai ne d 
hI D U A  e x pressi o n.  
I n t he pr o p os e d st u d y, s u bjects will be scree ne d f or ne utralizi n g  a nti b o dies t o A A V 2/ 6. S u bjects  
t hat test p ositi ve t o ne utralizi n g a nti b o dies t o A A V 2/ 6 will n ot be e nr olle d i n t his st u d y. 
Cell -me diate d i m m u nit y t o t he viral ca psi d m a y  be atte n uate d/ a br o ga te d wit h a c o urse of 
i m m u n os u p pressi o n si nce t he viral ca psi d is n ot e nc o de d i n t he vect or. T heref ore, i n t his st u d y, 
s u bjects will receive pretr eat me nt wit h oral pre d nis o ne or e q ui vale nt c ortic oster oi d  starti n g 2  da ys 
pri or t o t h e S B -3 1 8 i nf usi o n a n d as des cri be d i n A p pe n di x 3 . If a n y s u bject de vel o ps i ncrease d 
a mi n otransferases i n s pite of t he pre d nis o ne or e q ui vale nt c ortic oster oi d  tr eat me nt, t he pre d nis o ne 
or e q ui vale nt c ortic oster oi d  re gi me n ma y be a dj uste d or restarte d after c o ns ultati o n wit h t he 
Me di cal M o nit or (see A p pe n di x 3 ).  
8. 1. 1  P ote nti al O n -T ar get Effect  o n Al b u mi n  
Al b u mi n is  t he m ost a b u n da nt plas ma pr otei n, acc o u nti n g f or 5 5 -6 0 % of plas ma pr otei ns. T he t otal 
b o d y al b u mi n p o ol is a b o ut 2 5 0 t o 3 0 0 g f or a healt h y 7 0 k g a d ult , wit h a p pr o xi matel y 4 2 % of t his 
i n t he plas ma c o m part me nt a n d t he re m ai n der i n t he e xtra v asc ular s pace. T he latter is recirc ul ate d 
i nt o the vasc ular c o m p art me nt via t he l y m p hatics.  
Al b u mi n s y nt hesis i n h u ma ns occ urs o nl y i n t he li ver. T he rate of al b u mi n s y nt hesis i n a healt h y 
a d ult is 1 2-2 5 g/ d a y, b ut varies de p e n di n g o n t he n utriti o nal a n d healt h stat us of a n i n di vi d ual. T he 
ca pacit y t o i ncrease al b u mi n s y nt hesis is li mite d ( 2-2. 7 x n or mal) si nce m uc h of t he li ver s y nt hetic 
mac hi ner y is alr ea d y de v ote d t o al b u mi n s y nt hesis at rest.   
Dail y al b u mi n de gra dati o n is a p pr o xi matel y 1 4 g/ d or ~ 5 % of t otal b o d y pr ot ei n t ur n o ver. Al b u mi n  
is br o ke n do w n i n m ost or ga ns of t he b o d y , wit h 4 0 -6 0 %  bei n g d e gra d e d b y  m uscle a n d s ki n , 
~ 1 5 %  b y t he li ver, a n d ~ 1 0 % eac h  b y ki d ne y a n d gastr oi ntesti nal  tract.  
T he f u ncti o n of al b u mi n is well esta blis he d a n d i ncl u des mai nte na n ce of pl as ma o nc otic press ur e, 
aci d-bas e bala nce, a nti o xi da nt f u ncti o n, a n d a ntic oa g ula nt effects. Al b u mi n  als o bi n ds t o 
n u mer o us c o m p o u n ds , s uc h as h y dr o p h o bic or ga nic a ni o ns, l o n g c hai n fatt y aci ds, bilir u bi n, 
he mati n , a n d h or m o nes s uc h as t h yr o xi ne.  
Des pite t he i m p orta nce of al b u mi n, a p pr o x i matel y 3 0 i n di vi d uals wit h a nal b u mi ne mia ha ve bee n 
descri be d , i n w hic h m utati o ns i n the al b u mi n ge ne res ult i n m R N A s plici n g err ors a n d pre mat ure 
st o p c o d o ns (Wat ki ns  et al. 1 9 9 4 ). T hese s u bjects d o ha ve s o me cir c ulati n g al b u mi n ( < 1 g/ L), 
p ossi bl y  d ue t o ge ne lea k a ge. T he s u bjects’ b o dies a p pear t o c o m pe nsate b y sl o wi n g t he rate of 
al b u mi n de gra dati o n. S ur prisi n gl y, t hese s u bjects ha ve mi ni mal pat h ol o g y, li mite d t o peri p heral 
e de ma, li p o d ystr o p h y (l o wer li m b o besit y), fati g u e, a n d h y perli pi de mia (M i nc hi otti, et al. 2 0 1 3; 
Pri nse n &  va n der Vel de n 2 0 0 4;  Nic h ols o n et al. 2 0 0 0 ). T he he m o d y na mi c effects of 
a nal b u mi ne mia are mi n or, c o nsisti n g of a mi n or re d ucti o n i n o nc otic press ure ( 1 6 vs 2 5 m m H g) 
a n d arterial press ur e lea di n g t o i ncrease d re ni n a n d al d oster o ne secreti o n.  
Gi ve n t he rate of al b u mi n pr o d ucti o n b y t h e li ver ( 1 2 -2 5 g/ da y) , it ca n be esti mate d t hat c o n v ersi o n 
b y S B -3 1 8 of as little as  0. 0 1 % of al b u mi n alleles t o hI D U A s y nt hesis w o ul d  yiel d p ote ntiall y 
t hera pe uticall y be nefici al α-L -i d ur o ni dase le vels ( > 1 % of n or mal) i n p las ma (O uss ore n et al. 2 0 1 3; 
Al d uraz y me, E M A/ 2 0 1 5 ). T he l oss of s uc h a s mall pr o p orti o n of al b u mi n pr o d ucti o n is e x pecte d 
t o ha ve n o a d v erse c o ns e q ue nces. At t he i n di vi d ual cell l e vel, t he tar g ete d l oc us is c o m plet el y 
dis pe nsa b le, si nce al b u mi n has n o a ut ocri ne r ole. At t he or ga nis m le vel, heter oz y g o us disr u pti o n 
of al b u mi n yiel ds n o s y m pt o ms , a n d e v e n h o m oz y g o us disr u pti o n is t olerat e d as descri be d a b o ve. 

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T heref ore, disr u pti n g < 1 % of t he al b u mi n alleles is pre dicte d t o ha ve n o a d verse p h e n ot y pe.  
M ore o ver, gi ve n t he i ntr o nic l ocati o n of t he Z F N tar get site, Z F N clea v a ge a n d s u bse q ue nt D N A 
re pair i n t he a bse nce of h I D U A i nte grati o n (e. g., s mall i nserti o n a n d deleti o n m utati o ns at t he site 
of Z F N clea v a ge) will be f u ncti o na ll y i nert wit h res pect t o al b u mi n e x pressi o n. A rece nt re vie w of 
t he ge netic tar geti n g of t he al b u mi n l oc us t o treat he m o p hilia i n m uri ne m o dels hi g hli g hts  t he 
usef ul ness of tar geti n g a hi g hl y acti ve heter ol o g o us ge ne  li ke al b u mi n: n eit her tra nsa mi nitis n o r 
pert ur bati o ns i n ser u m al b u mi n le vels were o bser ve d , a n d fe w off -tar g et i nte grati o n sites were 
detecte d  (D a vi d off & N at h wa ni  2 0 1 6 ). 
8. 1. 2  P ote nti al Off -T ar get Effects  
A n u n biase d i nte grati o n site assa y was esta blis he d t o  i de ntif y Z F N clea v a ge sites a n d su bse q u e nt 
i nserti o n of a d o n or oli g o n ucle oti de d u ple x i n t he ge n o me (Ga briel et al. 2 0 1 1 ). T his assa y all o ws 
f or e val uati o n of all p ote ntial i nte grati o n sites wit hi n t he ge n o me. T he i nte grati o n site assa y wa s 
r u n usi n g t he S B-3 1 8 Z F Ns ( S B -4 7 1 7 1 a n d S B -4 7 8 9 8 ), a n d yiel de d a ra n ke d list of 3 9  ca n di date 
clea va g e sites. As e x pecte d, t he t o p ra n ke d l oc us i n t he h u ma n ge n o me wa s t he i nte n de d tar get site 
wit hi n al b u mi n i ntr o n 1. A f oll o w -u p i n d el a nal ysis perf or me d i n h u ma n pri mar y h e pat oc ytes 
tra ns d uce d wit h r A A V 2/ 6 e nc o di n g t h e S B -3 1 8  Z F Ns re veale d si g nifica nt m o dificati o n o nl y at 
t he o n-tar get site i n al b u mi n i ntr o n 1 (6. 1 % f or l o w d ose a n d 3 3. 5 % f or hi g h d ose) b ut  at n o ot her 
ca n di date clea va g e site.  
F or t he S B -FI X pr o gra m ( B B -I N D 1 6 7 2 1), w hic h uses Z F Ns hi g hl y si milar t o t he S B -3 1 8  Z F Ns , 
t he i nte grati o n site assa y re veal e d a si n gle, l o w acti vit y off -tar get site. D ue t o t he si milarit y of t he 
Z F N rea ge nts , t his off-tar get site was als o c o nsi dere d for f urt her a n al ysis i n t he S B -3 1 8  pr o gra m. 
T h e off -t ar get site w as ma p pe d t o e x o n 3 8 ( o ut of 4 8 e x o ns) of t he S M C H D 1  ge ne. S M C H D 1 has 
bee n li n ke d t o c hr o m os o me X -i nacti vati o n, t u m or s u p pressi o n, D N A da ma ge re p air, a n d 
faci osc a p ul o h u meral m usc ular d ystr o p h y t y pe 2 ( F S H D 2). 
A m o use k n oc k o ut ( b y ge netra p/ gt) of t he m uri ne h o m ol o g of S M C H D 1 has bee n g e nerate d 
(Ble witt et al. 2 0 0 8 ). Alt h o u g h  male k n oc k o ut mice  ( S mc h d 1 gt/ gt) de vel o p n or mall y, fe male 
k n oc k o ut mice  e x hi bit e m br y o nic let halit y d ue t o pr o ble ms wit h X c hr o m os o me i nacti vati o n a n d 
misre g ulati o n of C p G met h ylati o n. T his i n dicates a r ole f or S M C H D 1 i n e m br y o ge nesis i n t he 
fe male m o use, a n d s u g g ests t hat o nl y t he l oss of b ot h S M C H D 1 c o pies i n fe male patie nts c o ul d 
p ote ntiall y p ose a pr o ble m. F urt her m ore, it is u nclear w het h er X -i nacti vati o n w o ul d ha ve a n y 
i m pact o n li ver he pat o c ytes, w hic h are ofte n p ol y pl oi d. M ale k n oc k o ut mice s h o w n or mal 
e m br y o nic de v el o p me nt b ut i ncreas e d let halit y after birt h ( Le o n g et al. 2 0 1 3 ); sur vi vi n g mice 
a p pear n or mal a n d s h o w n o pre dis p ositi o n or s us ce pti bi lit y t o t u m or f or m ati o n. W he n  t h e male 
k n oc k o ut mice were cr osse d i nt o a pre mali g na nt E u -M yc tra ns g e nic m o use m o del, s o me 
he mat o p oietic ca n cers w ere det ecte d  i n h o m oz y g otes (Le o n g et al.  2 0 1 3 ). It has bee n s u g geste d 
t hat S M C H D 1 is recr uit e d t o t he site of D N A d a ma ge a n d t hat its de pleti o n c o ul d alter D N A 
da ma ge res p o nse si g nali n g a n d cell s ur vi val ( Ta n g et al. 2 0 1 4 ). H o we ver, n o e vi de nce f or 
decrease d cell s ur vi val or s p o nta ne o us acti vati o n of a p o pt osis (clea ve d Par p 1) or D N A da ma ge 
mar kers ( Ka p -1 p h os p h or y lati o n) was see n d uri n g i n vitr o d ose titrati o n st u dies wit h u p t o 4 5 % 
S B -3 1 8  Z F N o n -tar g et acti vit y.  
S M C H D 1 m utati o ns ha ve bee n ass ociat e d wit h faci osca p ul o h u meral m usc ular d ystr o p h y ( F S H D), 
w hic h is a n a ut os o mal d o mi na nt m usc ular d ystr o p h y affecti n g fac ial, s h o ul der gir dle, u p p er ar m, 
a n d ot her m uscl e tiss ues ( Lars e n et al. 2 0 1 5 ). F S H D t y pe 1 is li n ke d t o t he c o ntr acti o n of 
macr osatellite D 4 Z 4 re p eats a n d misre g ulati o n of t he D U X 4 tra nscri pt i n m y o blasts ( Statla n d &  

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Ta wil 2 0 1 4 ). T he far l ess c o m m o n F S H D t y pe 2 (a b o ut 5 % of all cases) has bee n li n ke d t o 
m utati o ns i n S M C H D 1 ( Le m mers et al.  2 0 1 2 ). H o we ver, S B-3 1 8  Z F N e x pressi o n s h o ul d b e 
restricte d t o he p at oc ytes d ue t o t he use of t he li ver-s pecifi c A p o E/ h A A T pr o m ot or, a n d n o li ver-
relate d s y m pt o ms ha v e b ee n re p orte d wit h F S H D. M ore o ver, i n viv o st u di es wit h t he s urr o gat e 
m o use S B -3 1 8  Z F Ns re veale d n o si g nifica nt m o dificati o n of t he al b u mi n l oc us i n tiss ues ot her 
t ha n li ver tiss ue, c o nfir mi n g t he Z F N’s  tiss ue-s p ecific e x pressi o n. 
D ose titrati o n st u dies carrie d o ut i n vitr o i n h u ma n he pat oc yt es wit h S B-3 1 8  Z F Ns s h o we d t hat 
t he S M C H D 1 off-t ar get site was m o difie d o nl y at l o w le vels, n earl y 1 0 0-f ol d bel o w t h ose o bs er ve d 
at t he al b u mi n  i ntr o n 1 o n -tar get site, a n d m o dificati o n le vels were ge n erall y wit hi n t he ra n ge s ee n 
i n m oc k-treate d cells or c o ntr ol sa m ples. O nl y at hi g her d oses of A A V 2/ 6 S B -3 1 8  Z F Ns, w hic h 
c orres p o n d e d t o a n o n -tar get acti vit y of m ore t h a n 2 0 %, were t he le vels of off-tar g et m o dificati o n 
at S M C H D 1 c o nsiste ntl y a b o ve bac k gr o u n d.  I n vitr o st u dies esta blis he d t hat n o n -h u ma n pri mate  
al b u mi n Z F N s urr o gate rea ge nts c ut t he c o ns er ve d S M C H D 1 off -tar get i n si milar fas hi o n wit h 
a b o ut 1 0 0 -f ol d less effici e nc y t ha n at t he al b u mi n o n-tar get l oc us. Acc or di n gl y, a nal ysis of n o n -
h u ma n pri mate  i n viv o s a m ples wit h o n-tar get Z F N acti vit y of u p t o 2. 1 % f o u n d n o si g nifica nt off-
tar get a cti vit y at t he S M C H D 1 l oc us. T hese res ults s u g gest t hat t he o bser ve d d ose-de p e n de nt off -
tar get acti vit y be ha vi or i n c ult ure d cells is pre dicti ve of t he i n viv o sit uati o n i n n o n -h u ma n pri mate s 
a n d p ote ntiall y h u ma ns.  
8 . 1.3  C arci n o ge nicit y  
T here is a ris k t hat pe o ple w h o recei ve g e ne tr a nsfer ma y d e vel o p t u m ors deri ve d fr o m t heir 
ge neticall y m o difie d cells. T his ris k has bee n see n wit h viral ge ne tr a nsfer vect ors t hat i nte grate 
ra n d o ml y i nt o t he cell ular D N A w here t he y ma y affect ge nes c o ntr olli n g cell  pr oliferati o n. T he 
rA A V 2/ 6 vect or d o n or will i nte grate  s pecificall y i n t he al b u mi n Z F N d o u ble -stra n d brea k site. I n 
t o xicit y st u dies, n o t u m ors were i d e ntifie d. F or e val uati o n of li ver carci n o ge nicit y , t he c urre nt  
st u d y a d o pts t he he pat o -cell ular carci n o ma  (H C C ) scree ni n g rec o m m e n dati o n f or hi g h ris k 
s u bjects (e. g., c hr o nic h e patitis C or B ), w hic h i ncl u des m o nit ori n g A F P  a n d li ver M RI. Li ver 
bi o ps y wi ll be p erf or m e d  if t here is a n a b n or mal A F P  a n d a > 2 c m  mass i n t he li ver  (El -Sera g & 
Da vila 2 0 1 1 ). 
8. 2  
Pre d nis o ne  ( or E q ui v ale nt C ortic oster oi d) 
Pre d nis o ne  is a gl uc oc ortic oi d. Gl uc oc ortic oi ds are a dre n oc ortical ster oi ds , b ot h nat urall y 
occ urri n g a n d  s y nt hetic, w hic h are rea dil y a bs or be d fr o m t he gastr oi ntesti nal tract.  
T he f oll o wi n g a d vers e reacti o n s ( A Rs) ha v e bee n  ass ociate d wit h t he use of gl uc oc ortic oi ds : 
•  T hi n ni n g of b o nes ( oste o p or osis) , w hic h ma y lea d t o fract ures or c o m pressi o ns, es peciall y 
tr ue of vert e bral b o dies ( bac k b o ne). 
•  L oss of bl o o d s u p pl y t o b o nes (ase ptic necr osis) , w hic h ma y ca use se vere b o ne pai n, 
fract ur es (es p eciall y of t h e hi p a n d s h o ul der), a n d w hic h  ma y re q uir e s ur gical c orrecti o n . 
•  Hi g h bl o o d press ure ( h y perte nsi o n) . 
•  I n crease d press ure i n t he e ye ( gla u c o ma) . 
•  Per ma ne nt cl o u di n g of visi o n i n o ne or b ot h e yes (cataracts) . 
•  Wei g ht gai n wit h i ncreas e d a p petite a n d fl ui d rete nti o n . 

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•  Faci al f ull ness . 
•  I n crease i n b o d y hair a n d ac ne, a n d te n de n c y t o eas y br uisi n g a n d t hi n ni n g of t he s ki n . 
•  I n crease d ris k of i nfecti o ns w hile o n hi g h d ose c o nti n u o us ster oi d t hera p y. 
•  I nterfere n ce wit h gr o wt h. 
•  M uscle cra m ps a n d j oi nt pai n . 
•  C ha n ges i n t he me nstr ual c ycle . 
•  Ele vati o ns i n b l o o d s u gar ( dia betes). 
•  S u p pressi o n of a dre n al gla n ds’ a bilit y t o ma ke necessar y c ortis o ne at ti mes of stress 
(a dre n al i ns ufficie n c y). 
•  Irritati o n of st o mac h a n d es o p ha g us wit h p ossi ble ulcer t y pe s y m pt o ms a n d, rarel y, 
blee di n g . 
•  E m oti o nal dist ur ba nces . 
Dietar y g ui deli nes will b e pr o vi de d t o s u bjects w hile o n pre d nis o ne or e q ui vale nt c ortic oster oi d  t o 
hel p alle viate s o me of t h e  si de effects i ncl u di n g bl o o d s u gar ele vati o n, ass ociate d wit h t he use of 
gl uc oc ortic oi ds  (refer t o t he St u d y Refere n ce M a n ual). 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
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             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 5 6  of 8 6  
9  
S T U D Y A S S E S S M E N T S  
9. 1  
Me dic al Hist or y  
A c o m plete me dical hist or y, i ncl u di n g c o n c o mita nt me dicati o ns , as well as a n y hist or y of graft -
vers us -h ost -diseas e i n s u bjects w h o ha ve h a d H S C T, will be o btai ne d t o assess st u d y eli gi bilit y. 
All cli nicall y -si g nifica nt me dical c o n diti o ns, s ur geries, a n d pr oce d ures s h o ul d be rec or de d. If t he 
s u bject is n ot n or mall y see n at t he st u d y ce nter, it ma y be necessar y t o o bt ai n me dical rec or ds t o 
c o nfir m st u d y eli gi bilit y.  F or details, refer t o t he St u d y Refere n ce M a n ual.  
9. 2  
De m o gr a p hics  
De m o gra p hic data o n eac h s u bject (e. g., a ge, g e n der, race, et h nicit y) will be o btai ne d at t he 
Scree ni n g visit.  
9. 3  
C o nc o mit a nt Me dic ati o ns  
C urre nt c o nc o mita nt me dicati o ns will be rec or de d.  F or d etails, refer t o t he St u d y Refere n ce 
Ma n ual.  
9. 4  
P h ysic al E x a m i n ati o n 
P h ysical e xa mi nati o ns will be c o n d ucte d o n eac h s u bject at t he s pecifie d visit a n d will i ncl u de at 
mi ni m u m: ge neral a p peara n ce, hea d, e yes, ears, n ose, a n d t hr oat ( H E E N T); as 
well as 
car di o vas c ular, d er mat ol o gic , res pirat or y, gastr oi ntesti nal, 
m usc ul os keletal, a n d n e ur ol o gic 
s yste ms. F or details, refer t o t he St u d y Refere n ce Ma n ual a n d t he P h ysical E xa m G ui deli nes.  
9. 5  
Vit al Si g ns  
Vital si g ns, i ncl u di n g hei g ht, wei g ht, s yst olic/ diast olic bl o o d press ur e, heart rat e, res pir at or y rate, 
a n d te m perat ure will be rec or de d . F or details, refer t o t he St u d y Refere n ce Ma n ual.  
9. 6  
J oi nt R a n ge of M oti o n  
Si nce M P S  I s u bjects are k n o w n t o s uffer fr o m j oi nt stiff ness, c o ntract ur es , a n d s k eletal 
def or mities, a series of j oi nt ra n ge of m oti o n ( J R O M) assess me nts will be c o n d ucte d , as per mitte d 
b y t he s u bject’s ca pacit y. F or d etails refer t o t h e St u d y Refere n ce M a n u al a n d t he P h ysical E xa m 
G ui deli nes . 
9. 7  
Ne ur ol o gic al Cr a ni al Ner ve E x a m a n d M uscle Stre n gt h Testi n g of U p per E xtre mities  
M utati o ns i n S M C H D 1, a ge ne i de ntifie d as a l o w -l e vel off tar get of S B-3 1 8, ha ve b ee n ass o ciate d 
wit h F S H D  (see Secti o n 8. 1. 2 ). N o detecta bl e m o dificati o n t o S M C H D 1 i n m uscle or ner ve cells 
b y S B -3 1 8 is e x pecte d at t he d oses use d  i n t his st u d y. Ne vert heless, f or safet y e val uati o n of S B-
3 1 8, f acial a n d u p per b o d y m uscle stre n gt h will be teste d , as per mitte d b y t he s u bject’s ca pacit y. 
F or details , refer t o t he St u d y Refere n ce M a n u al a n d t he P h ysical E xa m G ui deli nes . 
9. 8  
Electr oc a r di o gr a m  
1 2 -lea d E C Gs will be o btai ne d to m o nit or car diac f u ncti o n/c o n d ucti o n.  F or details, refer t o t he 
St u d y Refere nce Ma n ual.  
9. 9  
Ec h oc ar di o gr a m  
S ta n dar d 2-di me nsi o nal D o p pler E c h ocar di o gra ms ( E C H O s) will be o btai ne d t o e v al uate car di ac 
f u ncti o n. T he meas u re me nts will i ncl u de c ha m ber v ol u mes, ve ntric ular wall t hic k ness, left 

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             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 5 7  of 8 6  
ve ntric ular eje cti o n fracti o n, re gi o nal wall m oti o n, a n d val v ular m or p h ol o g y a n d f u ncti o n.  F or 
details, refer t o t he St u d y Refere n ce M a n ual a n d t he I ma gi n g G ui deli nes.  
9. 1 0  
C hest X -R a y  
C hest X -ra ys (als o k n o w n as A P ra di o gr a p h of t h e c h est) will b e o btai ne d t o e val uate t he g e neral 
healt h  a n d st u d y eli gi bilit y  of t he s u bject per t he Pri nci pal I n v esti gat or’s cli nical j u d ge me nt. F or 
details, refer t o t he I ma gi n g G ui deli nes.  
9. 1 1  
Pre g n a nc y T esti n g a n d C o ntr ace pti o n Re q uire me nts  
Pre g na nc y testi n g will be c o n d ucte d o n all fe mal e s u bjects of c hil d beari n g p ote ntial (f or details, 
refer t o t he La b orat or y M a n ual). 
A fe male s u bject is c o nsi dere d of c hil d beari n g p ote ntial (i.e., fertile) f oll o wi n g me n arc he a n d u ntil 
bec o mi n g p ost -me n o pa usal u nless per ma ne ntl y sterile. A p ost me n o pa usal state is defi ne d as n o 
me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca use. Per m a ne nt sterilizati o n met h o ds 
i ncl u de h ysterect o m y, bilateral sal pi n gect o m y, a n d bilateral o o p h orect o m y. 
Fe male s u bj ects of c hil d beari n g p ote ntial wit h a p ositi ve pre g na nc y test at Scree ni n g wil l n ot be 
e nr olle d i n t he st u d y.  
Fe male s u bjects of c hil d beari n g p ote ntial will ha ve a s er u m pre g na nc y test at t he S cree ni n g  a n d 
B aseli ne visit s. A u ri ne pre g na nc y test will be p erf or me d at Da y 0 if > 7 da ys fr o m Baseli ne  
pre g na nc y test i n g. S u bse q ue ntl y, uri ne  pre g na nc y tests will be d o ne at t he i n dicate d visits (see 
Secti o n 6 a n d A p pe n di x 1 ) u ntil at least 3 c o nsec uti ve plas ma  sa m ples after a d mi nistrati o n of S B -
3 1 8  are ne gati ve f or A A V 2/ 6 . A d diti o nal pre g na nc y tests will be p erf or me d at a n y visit at w hic h 
pre g na nc y stat us is i n q uesti o n. A  ser u m pre g n a nc y test will be perf or me d i n t he e ve nt of a p ositi ve 
or e q ui v ocal uri ne pre g n a nc y test res ult, or ca n be perf or m e d if pre g na n c y test b y uri ne is n ot 
feasi ble at t he discreti o n of t he Pri nci pal I n vesti gat or.  
Pre g na nc y i n a s u bject or a s u bjec t’s part ner m ust be re p ort e d t o t he S p o ns or (see Secti o n 1 0. 7 ).  
B ot h male a n d fe male se x uall y mat ure s u bjects m ust a gree t o use a barrier c o ntrace pti ve met h o d 
f or pre v e nti o n of A A V tra nsfer as f oll o ws: f or fe male s u bjects t his mea ns t hat t he s u bjects’ 
part ners m ust use a c o n d o m fr o m t he ti me of d osi n g wit h S B -3 1 8  u ntil  at least 3 c o nsec uti v e 
plas ma  sa m ples aft er a d mi nistrati o n of S B -3 1 8  are ne g ati ve f or A A V 2/ 6 ; f or male s u bjects t his 
mea ns t hat t he s u bjects  m ust use  a c o n d o m a n d m ust refrai n fr o m s per m d o nati o n fr o m t he ti me 
of S B -3 1 8  a d mi nistrati o n  u ntil at least 3 c o n sec uti ve se me n sa m ples aft er a d mi nistrati o n of S B -3 1 8  
are ne g ati ve f or A A V 2/ 6 . 
A d diti o nall y, fe male p artici pa nts of c hil d -beari n g p ote ntial w h o h a ve n ot u n der g o ne a t otal 
h ysterect o m y or bilateral sal pi n g o -o o p h orect o m y a n d w h o are se x u all y acti v e m ust c o ns e nt t o use 
a hi g hl y effecti ve met h o d of c o ntrace pti o n fr o m t he ti me of d osi n g wit h S B -3 1 8  u ntil at least 3 
c o nsec uti ve plas ma  sa m ples after a d mi nistrati o n of S B -3 1 8  are n e gati ve f or A A V 2/ 6 . E x a m ples 
of hi g hl y effecti ve met h o ds of c o ntrace pti o n i ncl u de:  
•  C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h 
i n hi biti o n of o v ulati o n (e. g., oral, i ntra va gi nal, tr a ns der mal). 
•  Pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n ass ociat e d wit h i n hi biti o n of o v ulati o n (e. g. oral, 
i njecta ble, i m pla nta ble).  
•  I ntr a uteri ne d e vice o r i ntra uteri ne h or m o ne-releasi n g s yste m.  

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Pa ge 5 8  of 8 6  
•  Bilateral t u bal occl usi o n .  
•  Male par t ner sterilizati o n (i.e., vasect o m y ).  
•  Se x ual a bsti ne nce (i.e., refrai ni n g fr o m heter ose x u al i nterc o urse d uri n g t he e ntire peri o d of 
ris k ass ociate d wit h S B -3 1 8 , w he n t his is i n li ne wit h t he preferre d a n d us ual lifest yle of 
t he s u bject). 
F or details, refer t o t he L a b orat or y Ma n ual . 
9. 1 2  
Cli nic al L a b or at or y Tests  
Cli nical la b orat or y tests are s u m mariz e d i n Ta ble 1 . F or det ails, refer  t o t he La b orat or y M a n ual. 
T a ble 1 .  
Cli nic al L a b or at or y Tests.  
He m at ol o g y  
C o m plete bl o o d c o u nt wit h 
differe ntial a n d platelet 
c o u nt 
Uri ne ( wit h micr osc o pic e xa mi nati o n) 
Gl uc ose  
Pr otei n  
Bilir u bi n  
Bl o o d  
p H  
S pecific gra vit y  
Ser u m C he mistr y  
S o di u m ( Na)  
P otassi u m ( K)  
C hl ori de ( Cl)  
Car b o nate ( C O 3 2 -) 
Calci u m ( Ca)  
P h os p hate ( P O 4 3 -) 
Bl o o d urea nitr o ge n  
Creati ni ne  
Gl uc ose  
Uric aci d  
L actate de h y dr o ge nase ( L D H)  
 
F or p e diatric c o h orts, ass ess me nts re q uiri n g bl o o d dra ws s h o ul d b e o btai ne d o ver m ulti ple da ys if 
nee de d t o e ns ure t hat n o greater t ha n 0. 8 m L/ k g of bl o o d is dra w n i n a n y 2 4 -h o ur peri o d.  
9. 1 3  
Li ver P a nel  
Li ver f u ncti o n testi n g will i ncl u de  assess me nt of A S T, A L T, t otal a n d direct bilir u bi n, al kali ne 
p h os p hatase, L D H, al b u mi n , a n d t otal pr otei n le vels. Si nce li ver f u ncti o n testi n g is i m p orta nt t o 
cl osel y m o nit or f or tra nsa mi nitis d ue t o A A V -me diate d i m m u n o ge nicit y i n t his st u d y, it is str o n gl y 
rec o m me n de d t hat s u bj ects refrai n fr o m c o ns u mi n g alc o h ol a n d fr o m ta ki n g li ver-t o xic 
me dicati o ns a n d her bal s u p ple me nts f or t he st u d y peri o d of o ne year after S B -3 1 8  a d mi nistrati o n. 
L i ver pa nel will be p erf or me d t wice a wee k f or at least t he first 2 0 wee ks p ost-S B -3 1 8 i nf usi o n , 
a n d ma y be c o n d ucte d re m ote l y. Bl o o d sa m ples f or li ver pa nel s hall be dra w n 2 t o 4 da ys a part 
w he n p ossi ble, e xc e pt f or t he first w ee k w he n t he y  will be dra w n o n t he Da y 1 a n d Da y 7 visits . 
S u bse q ue nt t o disc o nti n uati o n of pre d nis o ne or e q ui vale nt c ortic oster oi d, li ver pa n el will be 
perf or me d at all st u d y  visits f or t he d urati o n of t h e st u d y. Li ver pa nel d o es n ot nee d t o be dra w n 
as a se parate  bl o o d sa m ple if Cli nical La b orat or y T ests are o btai ne d at t he sa me visit . F or details, 
refer t o t he La b orat or y M a n ual. 
9. 1 4  
M P S I Ge ne Se q ue nci n g  
M P S I ge n e se q u e nci n g will be perf or me d at Scree ni n g t o c o nfir m t h e cli ni cal dia g n osis of M P S  I. 
T he assa y ma y b e perf or me d o n bl o o d or sali va s a m ples . F or p ost-tr a ns pla nt s u bjects, t he assa y 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 5 9  of 8 6  
will be perf or me d o n sali va sa m ples o nl y. F or p e diatric s u bjects (c o h orts 4  t hr o u g h 7 ), sali va 
sa m ples are str o n gl y pr eferre d. F or details, refer t o t he La b orat or y M a n ual . 
9. 1 5  
Si n gle -N ucle oti de P ol y m or p his m A n al ysis  
A S N P assa y will be perf or me d at Scree ni n g o n a bl o o d, b uccal, or sali va sa m ple t o i de ntif y 
p ol y m or p his ms i n t he Z F N -tar get e d re gi o n of t he al b u mi n l oc us. F or p ost -tra ns pla nt s u bjects, t he 
assa y will be p erf or m e d o n sali va sa m ples o nl y. F or pe diatric s u bj ects (c o h orts 4 t hr o u g h 7), sali va 
sa m ples are str o n gl y preferre d. S u bjects wit h p ol y m or p his ms i n t he Z F N -tar gete d re gi o n of t he 
al b u mi n l oc us  are n ot eli gi ble t o partici pate i n t his st u d y.  F or d etails, refer t o t h e La b orat or y 
Ma n ual . 
9. 1 6  
Vir al L o a d  
Testi n g f or HI V, H B V, a n d H C V will be c o n d ucte d  at Scree ni n g. S u bjects wit h a dia g n osis of HI V 
or e vi de nce of acti ve H B V or H C V i nfecti o n are n ot eli gi ble t o partici pate i n t his st u d y. F or details , 
refer t o t he La b orat or y M a n ual. 
9. 1 7  
Ne utr ali zi n g A nti b o dies t o A A V 2/ 6  
T he le vel of n e utralizi n g a nti b o dies t o A A V 2/ 6 will be meas ure d at Scree ni n g t o assess t he 
s u bject’s pre-e xisti n g i m m u ne res p o nse t o 
A A V 2/ 6.  S u bjects 
wit h ele vate d pre -e xisti n g 
ne utralizi n g a nti b o dies t o A A V 2/ 6 are n ot eli gi ble t o partici pate i n t his st u d y . F or details, refer t o 
t he La b orat or y M a n ual. 
9. 1 8  
C hi meris m Ass a y  
T he c hi meris m ass a y is a r o uti ne p ost -tr a ns pla nt m o nit ori n g t o ol t o e val uate t h e rati o of 
d o n or -t o-reci pie nt w hite bl o o d cell s i n peri p heral bl o o d. T he assa y will be perf or m e d o n bl o o d 
sa m ples i n p ost-H S C T s u bjects t o e val uate t he safet y of S B-3 1 8 wit h res pect t o a n y p ote ntial 
i m pact o n t he d o n or graft. Baseli ne c hi meris m pri or t o S B-3 1 8 will be esta blis he d b y a nal yzi n g 
bl o o d sa m ples i n c o nj u n cti o n wit h H S C T -d o n or s pecific a n d s u bject-s pecific ge netic mar k ers as 
pr o vi de d b y t he ori gi nal tra ns pla nt ce nter. I n i nst a nces w here t his dat a is n ot a vaila ble fr o m t he 
tra ns pla nt ce nt er, bas eli ne c hi meris m ca n be deter mi ne d fr o m b uccal s wa bs a n d peri p h eral bl o o d 
sam ples a nal yz e d i n parallel . F or details, refer t o t he La b orat or y Ma n ual.  
9. 1 9  
G A G Testi n g i n Uri ne a n d Bl o o d  
G A Gs are meta b olites t hat acc u m ulat e i n M P S I d ue t o lac k of acti ve I D U A  e nz y me. G A G 
acc u m ulati o n is res p o nsi ble f or diff use or ga n t o xicit y a n d da ma ge  i n M P S I. T o m o nit or t he effect 
of S B -3 1 8 a d mi nistrati o n, G A G le vels (i ncl u di n g t otal  G A G, D S G A G, a n d H S G A G)  will be 
meas ure d i n uri ne a n d tiss ues (i ncl u di n g bl o o d, li ver tiss ue, a n d C S F) t hr o u g h o ut t his st u d y. 
Sa m ples  f or G A G testi n g i n bl o o d a n d uri ne m ust be o btai ne d 7 d a ys aft er E R T  a d mi nistrati o n  ( +/- 
1 da y) a n d pri or t o t he ne xt E R T i nf usi o n . G A G a n d I D U A  le vels i n bl o o d will b ot h be meas ure d 
c o nc urre ntl y fr o m t he sa me bl o o d sa m ple. F or details, refer t o t he La b orat or y Ma n ual.  
9. 2 0  
Circ ul ati n g A F P  Le vel  
Cli nical la b orat or y m eas ure me nt of A F P will be perf or me d t o m o nit or f or p ote ntial de v el o p me nt 
of mali g na nc y. S u bjects wit h ele vate d a b n or mal circ ulati n g  A F P  at Scree ni n g are n ot eli gi ble t o 
partici pate i n t his st u d y . F or details, refer t o t he L a b orat or y Ma n ual.  

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
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Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 6 0  of 8 6  
9. 2 1  
Vect or Ge n o m e P C R  
P las ma, sali va, st o ol, a n d se me n ( m ales o nl y) sa m ples will be a n al yze d b y P C R t o deter mi ne 
cleara nce of S B -3 1 8  vect or ge n o mes . Eac h t y pe of sa m ple ( plas ma, sali va, uri ne, st o ol, se me n) 
s h o ul d be c ollecte d u ntil 3 c onsec uti ve s p eci me ns of t hat sa m ple t y pe are re p orte d as n e gati ve or 
u n detecta ble f or vect or g e n o me. C ollecti o n of se m e n  sa m ples m a y be wai v e d f or p e diatric s u bjects 
(c o h orts 4  t hr o u g h 7 ) at t he discreti o n of t he Pri nci pal In vesti gat or . F or details, refer t o t he 
La b orat or y M a n ual.  
9. 2 2  
P ul m o n ar y F u ncti o n Tests  
M P S  I is ofte n ass ociate d wit h si g nifica nt p ul m o nar y c o m plicati o ns. P ul m o nar y f u ncti o n tests 
(P F Ts ) are a c o m m o n m et h o d f or e val u ati n g res pirat or y f u ncti o n , a n d will be co n d ucte d in t his 
st u d y as per mitte d b y t he s u bject’s ca p acit y. F or details, refer t o t he St u d y Refere n ce M a n ual.  
9. 2 3  
6 -Mi n ute W al k Test  
A 6 -mi n ute wal k te st (6 M W T ) will be perf or me d, as per mitte d b y s u bject’s ca pacit y, t o meas ure 
e n d ura nce f oll o wi n g t h e A merica n T h oracic S ociet y G ui deli nes . F or det ails, refer t o t he St u d y 
Refere n ce M a n ual.  
9. 2 4  
Vis u al Ac uit y Test a n d C or ne al Cl o u di n g E x a m  
C or neal cl o u di n g a n d visi o n l oss are c o m m o n c o m plicati o ns of M P S  I. A sta n dar d vis ual ac uit y 
e xa m a n d i ns pecti o n of b ot h e yes wil l b e perf or me d t o deter mi ne t he a bse nce or prese n ce of 
c or neal cl o u di n g. F or d etails , refer t o t he St u d y Refere n ce 
Ma n u al a n d t he P h ysical E xa m 
G ui deli nes . 
9. 2 5  
Ne ur oc o g niti ve A bilities Tests  
W A SI -II, W P P SI -I V, a n d B SI D-III are wi del y -us e d ne ur oc o g niti ve test s t hat ha ve  bee n v ali date d 
a n d are easil y a d mi nistere d. Gi ve n t he br oa d a g e -ra n g e of st u d y partici p a nts a n d varia bilit y of 
C N S i n v ol ve me nt d ue t o M P S I , t he a p pr o priat e test will be deter mi ne d f or eac h s u bject at 
Scree ni n g f oll o wi n g a ne ur oc o g niti ve a bilities assess me nt. V A B S -II will be use d t o perf or m t he 
ne ur oc o g niti ve a bilities assess me nt. Base d o n t his i nitial e val uati o n, eit her t he W A SI -II, t he 
W P P SI -I V, or t he B SI D-III will be a d mi nistere d t o eac h s u bject be gi n ni n g at the Baseli ne visit. 
T he sa me test s h o ul d be use d t hr o u g h o ut t he st u d y d urati o n w he n p ossi ble t o all o w f or l o n git u di nal 
e val uati o n.  
T he V A B S -II test is gi ve n t o all s u bjects a n d pr o vi des a meas ure of a d a pti ve be ha vi ors, i ncl u di n g 
a bilit y t o c o pe wit h e n vir o n me ntal c ha n ges, t o lear n ne w s kills, a n d t o de m o nstrate i n de pe n de n ce.  
T h e tests will be a d mi nistere d b y a trai ne d ps yc h ol o gist or ps yc h o metrist  t o deter mi ne 
ne ur oc o g niti v e f u ncti o n o ver ti me after S B -3 1 8  a d mi nistrati o n , as per mitte d b y t he s u bject’s 
ca paci t y. F or det ails, refer t o t he St u d y Refere n ce Ma n ual. 
9. 2 6  
M RI of Li ver  
M RI of t he li ver is c o m m o nl y use d t o e val uate li ver pat h ol o g y i n patie nts  wit h M P S  I, a n d will be 
perf or me d  i n t his st u d y t o e val uate li ver a n d s plee n v ol u mes, as well as t o scree n a n d m o nit or  f or 
t he p ote ntial de vel o p me nt of li ver masses.  F or det ails, refer t o t he St u d y Refere nce Ma n ual a n d 
t he I m a gi n g G ui deli nes. 

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9. 2 7  
M RI of Br ai n a n d Cer vic al S pi ne  
M RI of t he brai n a n d cer vical s pi ne is c o m m o nl y use d t o e val uate 
ne ur ol o gical a n d s kel etal 
c o m plicati o ns i n patie nts wit h M P S  I, a n d will be perf or me d i n t his st u d y t o e val uate f or c ha n g es 
i n cli nical s oft tiss ue a n d/ or b o ne a p peara n ce.  T h e b aseli ne M RI of brai n a n d cer vical s pi ne ma y 
be o btai ne d at S cree ni n g (t o get her wit h M RI f or li ver) i nstea d of at B aseli ne at t he Pri nci pal 
I n v esti gat or’s discreti o n. F or details, refer t o t he St u d y Refere nce 
Ma n ual a n d t he I m a gi n g 
G ui deli nes.  
9. 2 8  
A dre n oc ortic otr o pic H or m o ne Sti m ul ati o n ( C os y ntr o pi n) Test  
A n A C T H sti m ulati o n test wil l be perf or me d pri or t o be gi n ni n g a n d disc o nti n ui n g a pre d nis o ne or 
e q ui vale nt c ortic oster oi d  re gi me n t o e val uate a dre n oc ortical f u ncti o n. D uri n g t he test, v ital si g ns 
s h o ul d be m o nit ore d a n d rec or de d e v er y h o ur. F or details, refer t o t he St u d y Refere n ce M a n ual.  
9. 2 9  
I D U A Testi n g i n Bl o o d   
I D U A acti vit y i n bl o o d will be meas ure d t o deter mi ne w het her I D U A is bei n g pr o d uce d a n d is 
acti ve. I D U A acti vit y meas ure m e nts ma y be c o n d ucte d o n plas ma , ser u m, w h ole bl o o d, drie d 
bl o o d s p ot, le u k oc ytes, or ot her bl o o d c o m p o ne nt. S a m ples m ust be o btai ne d 7 da ys after E R T 
a d mi nistrati o n ( +/- 1 d a y) a n d  pri or t o t he n e xt  E R T i nf usi o n.  I DU A  a n d G A G testi n g i n bl o o d 
will b ot h be meas ure d c o nc urre ntl y fr o m t he s a me bl o o d sa m ple. F or details, refer t o t h e 
La b orat or y M a n ual.  
9. 3 0  
Li ver Bi o ps y  
T he pr o p ose d mec h a nis m of acti o n of S B -3 1 8 is t o i ntr o d uce t he hI D U A tra ns ge ne i nt o a precise 
l ocati o n i n t he al b u mi n l oc us. T o deter mi ne t h e efficie nc y of S B -3 1 8 , li ver tiss ue will be o btai ne d 
b y  li ver bi o ps y, u nless c o ntrai n dicate d b y t he Pri nci pal I n v esti gat or or p h ysicia n, a n d a nal yze d b y 
hist o pat h ol o gic e xa mi nati o n, testi n g f or G A G le vels, a n d hi g h -t hr o u g h p ut se q ue nci n g of t he 
al b u mi n l oc us.  F urt her, s u bjects wit h a n ele va te d A F P or M RI m ass s us pici o us f or H C C or greater 
t ha n 2 c m will u n der g o li ver bi o ps y. Hist o pat h ol o gic e xa mi nati o n a n d ge n o mic a nal ysis will be 
perf or me d t o deter mi ne t he ori gi n a n d n at ure of t he t u m or. F or details, see  A p pe n di x 4  a n d refer 
t o t he St u d y Refere nce Ma n ual. 
9. 3 1  
L u m b ar P u nct ure  
M P S I ofte n ca uses ne ur oc o g niti ve decli ne d ue t o a b uil d u p of G A Gs i n t h e brai n. T o d eter mi ne if 
G A G le v els i n t he C S F are c h a n ge d after S B -3 1 8 a d mi nistrati o n, l u m bar p u n ct ures will be 
perf or me d o n all s u bjects, u nless c o ntrai n dicate d b y Pri nci pal I n v esti gat or or p h ysicia n. C S F 
sa m ples ma y als o be teste d f or cell c o u nt, t otal pr otei n, gl uc ose, a n d ot her 
M P S -relate d 
bi o mar kers . F or details, refer t o t he St u d y Refere n ce Ma n ual.  
9. 3 2  
I m m u n o ge nicit y Ass a ys  
E x pl orat or y researc h assa ys, i ncl u di n g t otal a nti b o dies t o 
A A V 2/ 6, Z F N , a n d I D U A 
i m m u n o ge nicit y will be perf or me d . At t he discreti o n of t he Pri nci pal I n vesti gat or, t his assess me nt 
ma y be wai v e d f or p e diatric s u bjects ( c o h orts 4  t hr o u g h 7 ) t o re d uce re q uire d bl o o d v ol u mes . F or  
details , refer t o t he La b orat or y Ma n ual. 
9. 3 3  
L a b or at or y Assess m e nts i n Pe di atric S u bjects  
Alt h o u g h safet y m o nit ori n g of s u bjects wit h cli nical la b orat or y testi n g is necessar y i n t his st u d y, 
t he p ote ntial i m pact of ta ki n g m ulti ple bl o o d sa m ples i n c hil dre n m ust be assesse d at all ti mes. 

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T heref ore, all bl o o d dra ws i n pe diatri c c o h orts s h o ul d be mi ni mize d w he n p ossi ble t o e ns ure t h e 
safet y a n d welfare of t he s u bjects, partic ularl y i n t he case of y o u n g er c hil dre n. I n acc or da n ce wit h 
acce pted g ui da nce, n o m ore t ha n 1 % of t otal bl o o d v ol u me ( 0. 8 m L/ k g) s h o ul d be dra w n i n 
pe diatric s u bjects i n a n y 2 4-h o ur peri o d  u nless me dicall y -i n dicate d bas e d o n t he j u d ge me nt of t he 
Pri nci pal I n vesti gat or ( V eal et al, 2 0 1 4 ). I n a d diti o n, it is e nc o ura ge d t o utilize pr oce d ures t o 
mi ni mize a n y pai n a n d distress ass ociate d wit h bl o o d sa m pli n g w he n p ossi ble, s uc h as use of 
i ntra ve n o us cat h eters, c ollecti o n fr o m ce ntral cat heters if i n place, a n d use of l ocal a n est hesia f or 
nee dle stic ks. F or details, refer t o t he La b orat or y Ma n ual . 
9. 3 4  
E R T A d mi nistr ati o n  L o g  
Fre q u e nc y of E R T a d mi nistrati o n will be st u die d bef ore a n d after a d mi nistrati o n of S B -3 1 8 . 
T heref ore, eac h d os e of E R T gi ve n t o t he s u bject fr o m t he ti me of Scree ni n g will be rec or de d o n 
t he E R T A d mi nistrati o n L o g b y st u d y staff  a n d will  i ncl u de date a n d ti me of start a n d st o p of E R T 
i nf usi o n. At eac h i n dicate d visit, d oc u me ntati o n of all E R T a d mi nistrati o n si nce t he last visit m ust 
be o btai ne d a n d c o nfir me d. A n ass u me d sta n di n g sc he d ule (e. g., wee kl y) s h o ul d n ot be use d.  
9. 3 5  
E R T Cli nic al Assess m e nt  
A cli nical assess me nt of t he nee d f or E R T m ust b e c o n d u cte d at t he E R T Wit h dra wal F oll o w -U p 
vis it. T he Pri nci pal I n v esti gat or s h o ul d deter mi ne if c hr o nic wee kl y E R T i nf usi o ns will be res u me d 
or if t he s u bject ma y c o nti n ue wit h o ut E R T, a n d i n dicate t he decisi o n o n t he a p pr o priat e e C R F. 
T he assess me nt will be ma de base d o n t he cli nical j u d ge me nt of t h e Pri nci pal I n vesti gat or a n d i n 
c o ns ultati o n wit h t he Me dical M o nit or, ta ki n g i nt o acc o u nt all i nf or mati o n a vaila ble ( w hic h ma y 
i ncl u de b ut is n ot li mite d t o A Es, cli nical la b orat or y testi n g, I DU A  le vels, G A G le vels, 6 M W T, 
P F Ts, a n d ot her a v aila ble data). T he E R T Cli nical Assess me nt ma y b e c o m plete d a gai n at a n y 
ti me p ost-E R T wit h dra wal if t here is a cli nicall y si g nifica nt c ha n ge i n t he stat us of t he s u bject’s 
E R T a d mi nistrati o n.  
 
 

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1 0  
S A F E T Y M O NI T O RI N G  A N D A D V E R S E E V E N T S  
1 0. 1  
Defi niti o ns  
1 0. 1. 1  A d verse E ve nt  
A n A E is a n y u nt o war d me dical occ urre n ce i n a patie nt or a cli nical trial s u bject a d mi nistere d a 
me dici nal pr o d uct. A n A E d oes n ot necessaril y ha ve a ca us al rel ati o ns hi p wit h t he a d mi nistere d  
treat me nt. T he ter m ca n  i ncl u de a n y of t he f oll o win g e ve nts t hat de vel o p or i ncrease i n se verit y 
d uri n g t he c o ur se of t his st u d y: 
•  A n y si g n, s y m pt o m, or p h ysical e xa mi nati o n fi n di n g t hat w orse ns i n nat ur e, se verit y, or 
fre q ue n c y c o m pare d t o Baseli ne, whet her t h o u g ht t o be relate d or u nrelate d t o t he c o n dit i o n 
u n der st u d y . 
•  A n y cli nicall y si g nifica nt la b orat or y a b n or malit y or la b orat or y a b n or m alit y t hat re q uir es 
me dicati o n or h os pitalizati o n . 
•  All reacti o ns ass oci ate d wit h t he use of  t he st u d y treat me nt, i ncl u di n g t h os e occ urri n g as a 
res ult of a n o ver d ose, a b use, wit h dra wal p h e n o me na, se nsiti vit y, or t o xicit y t o t he st u d y 
treat me nt. 
•  C o nc urre nt ill ness . 
•  I nj ur y or acci de nt. 
A pre -e xisti n g c o n diti o n is o ne t hat is pres e nt pri or t o or at t he st art of t he st u d y , a n d is t o be 
re p orte d as p art of t he s u bject’s me dical hist or y. It s h o ul d be re p orte d as a n A E  o nl y if t he 
fre q ue n c y, i nte nsit y, or t he c haracter of t he c o n diti o n w orse ns d uri n g st u d y partici pati o n . 
1 0. 1. 2  A d verse R e acti o n  
A n A R  is a n y u nt o war d a n d u n i nte n de d res p o ns e t o a me dici nal pr o d uct relate d t o a n y d ose 
a d mi nistere d. T he p hras e "res p o nse t o a me dici nal pr o d uct" mea ns t hat a ca us al relati o ns hi p 
bet wee n t he me dici nal pr o d uct a n d t he A R is at least a reas o na bl e p ossi bilit y (i.e., t here are 
facts/e vi de n ce or ar g u me nts t o s u g gest a ca usal rel ati o ns hi p).  
T he defi niti o n of a n A R als o c o v ers me di cati o n err ors a n d us es o utsi de w hat is f oresee n i n t he 
pr ot oc ol, i ncl u di n g mis use a n d a b use of t he pr o d u ct .  
1 0. 1. 3  U ne x pecte d A d ve rse E v e nt  or A d vers e Re a cti o n  
A n U ne x pecte d A E or U ne x pect e d A R  is a n A E or A R, t he nat ur e or s e verit y of w hi c h is n ot 
c o nsiste nt wit h t he refere nce safet y i nf or m ati o n ( R SI) f or t he pr o d uct (e. g., I n vesti gat or’s 
Br oc h ure) . 
1 0. 1. 4  Seri o us A d verse E ve nt  or Seri o us A d verse Re a cti o n  
A n  A E  or A R is c o nsi dere d “s eri o us” if, i n t he vie w of eit her t he Pri nci pal I n v esti gat or or t he 
S p o ns or , it res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  Deat h . 
•  Life -t hreate ni n g A E (i.e., A E i n w hic h t he s u bject was at ris k of deat h at t he ti me of t he 
e ve nt; it d oes n ot refer t o a n e v e nt w hic h h y p ot h eticall y mi g ht ha ve ca us e d deat h if it were 
m ore se vere).  

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•  I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n.  
•  Persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of a bilit y t o c o n d uct n or mal 
life f u ncti o ns. 
•  C o n ge nital a n o mal y/ birt h defect i n t he offs pri n g of a n e x p ose d s u bj ect.  
•  I m p ort a nt me dical e ve nt t hat ma y je o par dize t he s u bject or ma y re q uire a n i nter ve nti o n t o 
pre ve nt o ne of t he a b o ve c haracteristics/c o nse q u e n ces (i.e., e ve nt  ma y n ot res ult i n deat h, 
be life -t hr eate ni n g, or re q uire h os pitalizati o n, b ut b ase d o n a p pr o priate me di cal j u d g me nt, 
it ma y je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 
o ne of t he o utc o mes liste d a b o ve; exa m ples i n cl u de aller gic br o nc h os pas m re q uiri n g 
i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat 
d o n ot res ult i n i n p atie nt h os pita lizati o n, a n d d e v el o p me nt of dr u g de p e n de nc y or dr u g 
a b use). 
Wit h re gar d t o res ults o btai ne d fr o m tests i n la b orat or y a ni mals or i n vitr o testi n g, w het her or n ot 
c o n d ucte d b y Sa n ga m o , a S A E  i ncl u des a n y e v e nt s u g gesti n g si g nifica nt ris k t o h u ma n s u bjects. 
1 0. 1. 5  S us pecte d U ne x pecte d Seri o us A d verse Re a cti o n  
A s us pecte d u ne x p ecte d seri o us a d v erse reacti o n ( S U S A R) is a n y S A E t hat is assess e d as b ot h 
u ne x pecte d a n d, i n t he vi e w of eit her t he Pri nci pal I n v esti gat or or t he S p o ns or , as a n A R.  
1 0 . 2 
A d verse E ve nt R e p orti n g Peri o d   
A E s will be m o nit ore d c o nti n u o usl y d uri n g t he st u d y fr o m t he ti me t hat t he s u bject has pr o vi de d 
writte n i nf or me d c o nse nt t hr o u g h t he s u bject’s last da y of st u d y partici p ati o n. S u bjects will be 
q uerie d a n d e ve nts will be assesse d at eac h cl i nic visit. A treat me nt -e mer g e nt A E ( T E A E) is a n y 
A E wit h a n o nset fr o m a n y ti me fr o m a d mi nistrati o n of t he st u d y treat me nt t hr o u g h t he last st u d y 
visit , w het her or n ot it is c o nsi dere d ca usall y relat e d t o t he st u d y treat me nt.  
1 0 . 3 
Rec or di n g of a n A d vers e E ve nt  
T he Pri nci pal I n vesti gat or is res p o nsi ble f or e val u ati n g all A E s, o btai ni n g s u p p orti n g d oc u me nts, 
a n d deter mi ni n g t hat d oc u me ntati o n of t he e ve nt is a de q uate.  He/s he is res p o nsi ble f or deter mi ni n g 
t he se verit y of t he A E a n d its relati o ns hi p to t he i n vesti gati o nal dr u g. T he Pri nci pal In v esti gat or 
ma y dele gate t h ese d uties t o s u b -i n vesti gat ors b ut  m ust ass ure t hat t hese s u b -i n vesti gat ors are 
q ualifie d t o perf or m t hese d utie s u n der t he s u per visi o n of t he Pri nci pal In v esti gat or.  
All A E s will be re c or de d i n t he s u bject’s C R F. T he detaile d descri pti o n of t he e ve nt will i ncl u de 
a p pr o priatel y gra de d se v erit y of t he A E  a n d its rel ati o ns hi p t o t he i n vesti gati o nal pr o d uct. Se verit y 
will be cate g oriz e d b y t o xicit y gra de acc or di n g t o t he C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts ( C T C A E) Versi o n 4. 0 3. 
A E s n ot liste d i n t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts versi o n 4. 0 3 will be 
e val uate d b y usi n g t he f oll o wi n g criteria:  
•  Gra de 1, 
Mil d: S y m pt o ms ca use  n o or mi ni mal i nterfere nce wit h us ual s ocial a n d  
f u ncti o nal acti vities. 
•  Gra de 2, M o derate:  S y m pt o ms ca use greater t ha n mi ni mal i nterfere n ce wit h us ual s ocial 
a n d f u ncti o nal a cti vities. 

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•  Gra de 3, Se vere:  S y m pt o ms ca use  i nabilit y t o perf or m us ual s ocial a n d  f u ncti o nal 
acti vities. 
•  Gra de 4, P ote ntiall y Li fe-t hreate ni n g: S y m pt o ms ca use i na bilit y t o perf or m basic self-care 
f u ncti o ns 
O R 
me dical or o perati ve i nter ve nti o n i n dicate d t o pre v e nt per ma n e nt 
i m pair me nt, persiste nt disa bilit y, or deat h . 
•  Gra de 5: O utc o me of A E is deat h . 
T he relati o ns hi p of t h e A E  t o t he i n vesti gati o nal dr u g will be d eter mi ne d b y t he Pri nci pal 
In v esti gat or . A n y A E  t hat d oes n ot meet t he defi niti o n of a s us pecte d A R  will be cate g orize d as 
N ot Relate d . 
A n y G ra d e 3 a n d 4 cli nic al la b orat or y res ults t hat re pres e nts a n i ncreas e i n se verit y fr o m B as eli ne 
will be re p orte d as a n A E  if it is n ot ass ociate d wit h a dia g n osis alrea d y re porte d o n t he C R F . A 
G ra de 1 or 2 cli nical l a b orat or y a b n or malit y s h o ul d be re p orte d as a n A E  o nl y if it is c o nsi dere d  
cli nicall y si g ni fica nt b y t he Pri nci pal In vesti gat or.  
I n t he e v e nt of deat h, t he ca use of deat h s h o ul d be rec or de d as t he A E  a n d re p orte d as a S A E.  
“ Deat h ” is n ot t he A E ; “ deat h” is a n o utc o me. T he ter m “deat h ” s h o ul d be re p orte d as a n S A E 
o nl y if t he ca use of deat h is n ot k n o w n a n d ca n n ot be deter mi ne d.  If a n a ut o ps y is perf or m e d, a 
c o p y of t he a ut o ps y re p ort s h o ul d be o btai ne d if p ossi ble.  T he Pri nci pal I n v esti gat or s h o ul d ma ke 
e ver y eff ort t o o btai n a n d se n d deat h c ertificat es a n d a ut o ps y re p orts t o Sa n ga m o . 
1 0. 4  
Seri o us A d verse E ve nt Re p orti n g Peri o d  
All S A E s, w het her or n ot u ne x pecte d or c o nsi dere d t o be ass ociate d wit h t he a d mi nistrati o n of  S B -
3 1 8 , m ust be re p orte d i m me diatel y t o Sa n ga m o or its desi g nees b y tele p h o ne or fa x, a n d m ust be 
s u b mitte d t o Sa n ga m o or its desi g nees o n a n S A E Re p ort f or m wit hi n 2 4 h o urs of t he Pri nci pal 
I n v esti gat or’s disc o ver y of t he e ve nt. Please refer t o t he S t u d y R efere nce M a n ual f or S A E 
re p orti n g g ui deli nes a n d c o ntacts. 
T he re p orti n g peri o d f or all S A Es is fr o m s u bject c o nse nti n g t hr o u g h t he last st u d y visit.  
T he Pri nci pal I n vesti gat or is res p o nsi ble f or pr o m ptl y n otif yi n g t he I R B/I E C or e q ui v ale nt i n 
acc or da nce wit h l ocal re g ulati o ns  of all S A Es . T he Nati o nal I nstit utes of Healt h ( NI H) re q uires 
t hat all i n vesti gat ors p arti ci pati n g i n ge n e tr a nsfer researc h t o re p ort all S U S A Rs . S U S A Rs  will be 
re p orte d t o t he a p pr o priate  re g ul at or y aut h orities ( F D A / M H R A or e q ui val e nt) acc or di n g t o t he 
re q uire me nts f or e x pe dite d safet y re p orti n g. Sa n ga m o  or its desi g nee  will ass u me t he res p o nsi bilit y 
f or re p orti n g S U S A Rs  t o t he F D A/ M H R A or e q ui vale nt .  
All “seri o us” e ve nts m ust be f oll o we d wit h a p pr o priate me dical ma na g e me nt u ntil res ol ve d or 
sta bilize d.  
1 0. 5  
Rec or di n g of a Seri o us A d verse E ve nt  
S A Es  re p ort e d b y tele p h o ne m ust be rec or de d o n a writte n S A E  Re p ort F or m pr o vi de d b y 
Sa n ga m o  or its desi g nees . T he S A E re p ort f or m m ust be s u b mitte d t o Sa n ga m o  or its desi g nees 
wit hi n 2 4 h o urs.  
T he Me dical M o nit or will t he n a d vise t he Pri nci pal I n vesti gat or re gar di n g t he nat ure of a n y f urt h er 
i nf or mati o n or d oc u m e ntati o n t hat is re q uire d. F oll o w -u p re p orts m ust be s u b mitte d wit hi n 
2 4  h o urs fr o m t he ti me t hat t he a d diti o nal i nf or mati o n bec o mes a vaila bl e.  

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 6 6  of 8 6  
1 0. 6  
S U S A R Re p orti n g O bli g ati o ns  
Sa n ga m o or its desi g ne e will s u b mit S U S A R re p orts t o a p pr o p riate re g ulat or y aut h orities 
(i ncl u di n g C o m pete nt A ut h orities i n all 
Me m ber States c o n cer ne d), Et hics C o m mittees, a n d 
Pri nci pal I n vesti gat ors as per l ocal la ws a n d re g ulati o ns. Fatal a n d life -t hreate ni n g S U S A Rs will 
be s u b mitte d n o later t ha n 7 cale n d ar d a ys of first k n o wle d ge of t h e e ve nt, a n d f oll o w -u p 
i nf or mati o n will be s u b mitte d wit hi n a n a d diti o nal 8 da ys. All ot her S U S A Rs will be s u b mitte d 
wit hi n 1 5 cale n dar da ys of first k n o wle d ge of t he e ve nt.  
Pri nci pal I n vesti gat ors are re q uir e d t o re p ort a n y ur ge nt safet y matters t o Sa n ga m o or its desi g ne e 
wit hi n 2 4 h o urs. Sa n ga m o o r its desi g nee will i nf or m t he re g ulat or y a ut h orities, et hics co m mittees, 
a n d Pri nci pal I n v esti gat ors of a n y e v e nts (e. g., c h a n ge t o t he safet y pr ofile of t he st u d y treat me nt, 
maj or safet y fi n di n gs) t h at ma y o cc ur d uri n g t he cli nical trial t hat d o n ot fall wit hi n t he defi niti o n 
of a S U S A R b ut ma y affect t he s afet y of s u bjects partici pati n g i n t he cli nical trials, as re q uire d, i n  
acc or da nce wit h a p plica ble la ws a n d re g ulati o ns. T he re p orti n g peri o d f or ur ge nt safet y iss ues is 
t he peri o d fr o m t he si g ni n g of t he I C F t hr o u g h t he last st u d y visit.  
T he Pri nci pal I n vesti gat or will n otif y t he I R B/I E C or e q ui vale nt of S A Es a n d ur ge nt saf et y matters, 
i n acc or da n ce wit h I R B/I E C or e q ui vale nt re q uire me nts a n d l ocal la ws a n d re g ulati o ns. A c o p y of 
t his n otificati o n m ust be pr o vi de d t o Sa n ga m o or its desi g nee. 
1 0. 7  
Pre g n a nc y a n d Pre g n a nc y of a P art ner Re p orti n g  
Pre g na ncies or pre g n a ncies of pa rt ners occ urri n g d uri n g t his st u d y are t o be re p orte d o n t he 
Pre g na nc y Re p orti n g F or m. I n g e neral, it is e x pecte d t hat pre g na n cies are  re p ort e d i n t he sa me 
ti mefra me as S A Es. Re g ar dless of w h et her t he s u bject has disc o nti n ue d partici pati o n i n t he st u d y, 
t he c o urse of all pre g n a n cies a n d a n y A Es will be f oll o we d t o part u m at mi ni m u m . 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 6 7  of 8 6  
1 1.  
T R E A T M E N T S C H E D U L E, D O S E E S C A L A TI O N , A N D S T O P PI N G R U L E S  
1 1 . 1 
Sc he d ule f or S u bject Tre at me nt  
S u bjects w h o satisf y all eli gi bilit y  criteria will be e nr olle d i nt o o n e of t h e f oll o wi n g treat me nt 
c o h orts as descri be d bel o w : 
 
C o h ort #  
A ge R a n ge 
( y) 
T ot al D ose 
( v g/ k g) 
# S u bjects  
1  
≥1 8  
1. 0 0 E + 1 3  
1  
2  
≥1 8  
5. 0 0 E + 1 3  
2  
3  
≥1 8  
1. 2 0 E + 1 4  
2  
4  
1 2 -1 7  
T B D  
2  
5  
1 2 -1 7  
T B D  
2  
6  
5 -1 1  
T B D  
2  
7  
5 -1 1  
T B D  
2  
 
F or eac h d ose c o h ort after C o h ort 1, t w o s u bjects will be d ose d ≥ 4 wee ks a part. S M C re vie w will 
occ ur after all s u bjects i n eac h c o h ort ha ve ≥ 4 wee ks of safet y data .  
T he pe diatri c c o h orts will be e nr olle d o nl y aft er re vie w of c u m ulati ve a d ult s afet y dat a b y t he S M C 
(see Secti o n 1 2. 3 ). T he starti n g d ose f or pe diatric c o h orts 4  t hr o u g h 7 will be deci de d base d o n 
S M C re vie w of st u d y data, a n d m ust meet pre -defi ne d safet y criteria (see Pe diatric D osi n g). 
A p pr o xi matel y 2 a d diti o nal s u bjects ma y be a d de d t o a n y c o h ort after S M C re vie w  of st u d y d ata 
if safet y criteri a are met (see Safet y M o nit ori n g C o m mittee), wit h u p t o a t otal of 27  s u bjects i n 
t he st u d y. 
1 1 . 2 
D ose Esc al ati o n R ules  
Wit hi n eac h c o h ort, treat me nt will be sta g gere d s o t hat eac h s u bse q ue nt s u bject will n ot be i nf use d 
u ntil t he prece di n g s u bject has bee n o bser ve d f or at least 4 wee ks f ol l o wi n g a d mi nistrati o n of 
S B -3 1 8 .  
D ose escalati o n t o t he ne xt c o h ort will n ot occ ur u ntil at least 4  wee ks after t he last s u bject i n t he 
prece di n g c o h ort has b ee n d ose d , t he safet y data fr o m t he pri or c o h ort has bee n re vie we d b y t he 
S M C, a n d t he S M C has a gree d t o d ose escalat e .  
D osi n g a n d d ose escal ati o n will be pa use d if a Gra de 3 or hi g her A E occ urs,  or  if t w o Gra de 2 A Es 
occ ur wit hi n t he sa me or ga n class a n d p ersist  f or m ore t ha n 2  wee ks wit h t hera p y, pr o vi de d t hese 
A Es are n ot rel ate d t o t h e pri mar y M P S I dise ase or treat me nt of t he M P S I disease. I n s uc h a n 
e ve nt, t he S M C will be c o n ve ne d t o assess f or p ote ntial d ose -li miti n g t o xicit y (D L T ), a n d t o 
pr o vi de rec o m me n d ati o ns o n w het her  t o e x pa n d t he c o h ort at t he sa me d ose le vel,  t o d ose 
de -escalate, or t o c o nti n ue t he st u d y as pla n ne d (refer t o t he St o p pi n g R ules). 
1 1. 3  
Pe d i atric D osi n g 
Pe diatric d osi n g will n ot be i nitiate d u ntil a d ult safet y data has b ee n o btai ne d a n d re vie we d b y t he 
S M C, a n d o nl y after t he f oll o wi n g c o n diti o ns ha ve bee n met:  
•  ≥6 m o nt hs of safet y data fr o m 2 a d ults treate d wit h S B -3 1 8 at a n y d ose; a n d  
•  ≥4 we e ks of safet y data fr o m 2 a d ults treate d wit h S B -3 1 8  at t he i nte n de d pe diatric d ose. 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 6 8  of 8 6  
Y o u n ger pe di atric s u bjects ( C o h orts 6  a n d 7 ) ma y n ot be d ose d u ntil ol der pe diatri c s u bjects 
( C o h orts 4  a n d 5 ) ha ve b ee n d ose d at t he s a me d ose le vel, a n d ≥4 wee ks of safe t y data fr o m eac h 
ol der s u bject has bee n re vie we d b y t he S M C.  
1 1. 4  
E R T Wit h dr a w al  
E R T is be neficial b ut has si g nifica nt dra w bac ks, i ncl u d i n g the nee d f or c o nti n u o us life -l o n g 
treat me nt, de v el o p me nt of ne utralizi n g a nti b o dies , lac k of effi cac y i n t he brai n ( d ue t o i na bilit y t o 
cr oss t he bl o o d -brai n barri er) , c o nti n ue d car diac, 
m usc ul os keletal, a n d u p p er air wa y 
c o m plicati o ns , a n d t he i nc o n ve nie nce a n d c ost of wee kl y I V i nf usi o ns (T o ma ni n et al, 2 0 1 4 ). 
T he g oal of S B -3 1 8  tr eat me nt is t o a br o gat e or d ecre ase t he nee d f or E R T  b y usi n g e n gi n eere d 
Z F Ns t o site -s pecificall y i nte grate a c orrecti ve c o p y of a hI D U A  tr a ns ge n e i nt o t he ge n o me of t he 
s u bject's o w n he pat oc yt es i n viv o, res ulti n g i n life-l o n g, li ver-s pecifi c e x pressi o n  of h I DU A .  
S u bjects w h o ha ve recei ve d S B -3 1 8  ma y n o l o n ger re q uire wee kl y a d mi nistrati o n of E R T, a n d 
ma y be c o nsi dere d f or wit h dra wal of E R T (if a p plica ble).  
E R T wit h dra wal will be a c o ntr olle d pr ocess , wit h a d diti o nal safet y m o nit ori n g t o re d uce p ote ntial 
ris ks t o t he s u bject, a n d is an o pti o nal part of t he st u d y . 
E R T wit h dra wal ma y be i nitiate d b y t he Pri nci pal I n vesti gat or after c o ns ultati o n wit h t he S p o ns or, 
a n d o nl y i n s u bjects w h o  are willi n g a n d w h o meet all of t he f oll o wi n g criteria : 
•  are ≥1 2 w ee ks p ost -a d mi nistrati o n of S B -3 1 8 ; 
•  are m e dicall y sta ble a n d ca n t olerate te m p orar y disc o nti n uati o n of E R T i n t he j u d ge me nt of 
t he Pri nci pal I n vesti gat or; a n d 
•  agree t o a d diti o nal safet y m o nit ori n g a n d cli nical la borat or y  tests u ntil t he E R T W it h dra wal 
F oll o w -U p visit (see A p p e n di x 2 ). 
St u d y visits ass ociate d wit h E R T wit h dra wal m a y occ ur c o nc urre nt  wit h  or i n de pe n de nt of re g ul ar 
sc he d ule d st u d y visits, b ut s h o ul d be c o m bi ne d wit h re g ular sc he d ule d st u d y visits w he ne ver 
p ossi ble t o re d uce st u d y  b ur de n. W he n c o m bi ne d, assess me nts ass ociate d wit h E R T wit h dra wal 
t hat are d u plicate d at t h e re g ular s c he d ule d st u d y visits s h o ul d be wai ve d ( see A p pe n di x 1 ). T he 
E R T Wit h dra wal F oll o w -U p visit ca n o cc ur at a n y ti me u p t o 1 2  wee ks after E R T wit h dra wal at 
t he discreti o n of t he Pri n ci pal I n vesti gat or. 
E R T d oes n ot nee d t o be restarte d after t he E R T Wit h dra wal F oll o w -U p visit. H o we ver, E R T ma y 
be re -i nitiate d at a n y ti me base d o n cli nical circ u msta nces or at t he j u d ge me nt of t he Pri nci pal 
I n v esti gat or.  
E R T w it h dra wal ma y be re peat e d if pre vi o usl y u ns uccessf ul. H o we v er, E R T wit h dra wal ma y n ot 
be atte m pte d u ntil  at least 1 2 wee ks after E R T has bee n res u me d , a n d o nl y at t he discreti o n of t he 
Pri nci pal I n vesti gat or i n c o ns ultati o n wit h t he S p o ns or.  S u bjects u n der g oi n g re peat E R T 
wit h dra wal m ust be willi n g a n d meet t he criteria f or i nitial E R T wit h dra wal liste d a b o ve.  
D oc u me ntati o n of d osi n g a n d a d mi nistrati o n of all E R T s h o ul d be o btai ne d a n d rec or de d o n t he 
E R T ad mi nistrati o n lo g.  
1 1 . 5 
St u d y St o p pi n g R ules  
T he s afet y data f or all s u bjects wit h i n a c o h ort will be e val uat e d b y t he  S M C at least 4  wee ks  after 
t he last s u bject wit hi n t hat c o h ort was i nf use d wit h S B-3 1 8. Saf et y data i ncl u di n g A E s a n d cli nical 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 6 9  of 8 6  
la b orat or y test res ults (c he mistr y, he mat ol o g y, etc.) will be e val uate d t o d eter mi ne if it is safe t o 
d ose escal ate.   
S u bjects i n t he s u bse q ue nt c o h ort ma y be scree n e d a n d e nr olle d pri or t o t he safet y re vie w  b ut  will 
n ot be i nf use d u ntil t he S M C has  re vie we d t h e dat a a n d a p pr o ve d t he st u d y f or c o h ort es calatio n.  
T he S M C will als o be c o n ve ne d t o rec o m me n d w het her t he st u d y s h o ul d b e st o p pe d if a n y of t h e 
f oll o wi n g criteria are met:  
•  A n y o ne Gra de 3 or hi g h er  A E , or a n y t w o Gra d e 2 A E s i n t he sa me s yste m or ga n class 
t hat last more t ha n 2 wee ks wit h t hera p y, pr o vi de d  t hese A E s are n ot relate d t o t he pri mar y 
M P S I  disease or treat me nt of t he M P S I  diseas e.  
•  S A E n ot relate d t o t he pri mar y M P S I diseas e   
•  Deat h of a s u bj ect . 
•  De vel o p me nt of a  m ali g na nc y . 
T he st u d y ma y als o be st o p pe d f or a n y of t he f oll o wi n g reas o ns:  
•  Sa n ga m o , i n c o ns ultati o n wit h t he S M C or Re g ulat or y A ge n c y,  deci des f or a n y reas o n t hat 
s u bject safet y ma y b e c o m pr o mise d b y c o nti n ui n g t he st u d y. 
•  Sa n ga m o  deci des t o disc o nti n ue de vel o p me nt of S B -3 1 8 . 
If st o p pi n g criteri a are met, n o f urt her d osi n g of s u bjects will be p erf or me d u ntil a s u bsta ntial 
a me n d me nt is s u b mitte d t o t he re g ulat or y a ut h orit y(ies) f or re vi e w, a n d t he a me n d me nt has bee n 
a p pr o ve d b y t he site I R B/I E C or e q ui vale nt.  W he n n o f urt her e nr olli n g or d osi n g decisi o ns are 
re q uire d of t he S M C, t he S M C will n o l o n ger meet. Sa n ga m o will re vie w s u bject safety data o n 
a n o n g oi n g basis.  
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 7 0  of 8 6  
1 2  
S U B J E C T WI T H D R A W A L/ DI S C O N TI N U A TI O N, A N D S A F E T Y 
M O NI T O RI N G C O M MI T T E E  
1 2 .1  
S u bject Wit h dr a w al a n d Disc o nti n u ati o n fr o m St u d y  
S u bjects  ma y wit h dra w or  s h o ul d be disc o nti n ue d fr o m st u d y f or a n y of t h e f oll o wi n g reas o ns:  
•  Re q ue st b y t he s u bject t o wit h dra w . 
•  Re q uest of Sa n ga m o  or pri mar y care pr o vi der if h e or s he t hi n ks t he st u d y is n o l o n ger i n 
the best i nterest of t he s u bject . 
•  Pre g na nc y  pri or t o  S B -3 1 8  i nf usi o n. 
•  S u bject j u d ge d b y t he Pri nci pal I n vesti gat or t o be at si g nifica nt ris k of faili n g t o c o m pl y 
wit h t he pr o visi o ns of t h e pr ot oc ol as t o ca us e har m t o self or s eri o usl y i nterfere wit h t h e 
vali dit y of t he st u d y res ults . 
•  At t he discreti o n of t he I R B/I E C or e q ui vale nt, Office f or H u ma n Res earc h ( O H R), 
re g ulat or y aut h orit y ( e. g., F D A/ M H R A  or e q ui vale nt),  Pri nci pal I n vesti gat or, or Sa n ga m o . 
S u bjects will be str o n gl y e nc o ura g e d t o c o nti n ue a n d c o m pl y wit h f oll o w -u p safet y e val u ati o ns . If 
a s u bject wit h dra ws c o nse nt or disc o nti n ues fr o m t he st u d y p o st-st u d y treat me nt, a c o nfere nce 
bet wee n t he Pri nci pal I n vesti gat or a n d Me dical M o nit or will ta ke place t o e ns ure t hat t he s u bj ect 
u n dersta n d s t he i m p orta n ce of t he st u d y f oll o w-u p a n d t hat t he st u d y treat me nt ca n n ot be re v erse d 
e ve n if a s u bject dr o p s o ut of t he st u d y f oll o w -u p . If t he s u bject a grees, a re d uce d f oll o w-u p testi n g 
sc he d ule ma y b e arra n g e d i ncl u di n g tele p h o ne call a n d safet y la bs t o  assess  treat me nt-relate d A E s 
a n d disease stat us.  
1 2 . 2  S afet y M o nit ori n g a n d Miti g ati o n Pl a n  
T he li ver f u ncti o n (t otal a n d direct bilir u bi n, al kali ne p h os p hatase, A L T, A S T, L D H, al b u mi n, a n d 
t otal pr otei n) of st u d y s u bjects will be m o nit ore d cl osel y t hr o u g h o ut t he st u d y as i n dicate d a b o ve 
i n Secti o n 9. 1 3 .  
Ke y p ote ntial a ntici pate d ris ks are:  
•  De vel o p me nt of  tra nsa mi nitis d ue t o cell-me diate d i m m u nit y t o t he A A V ca psi d pr otei n, 
t he e n gi neere d Z F Ns, or t he hI D U A  d eli vere d b y S B -3 1 8 ; to mi ni mize t he p ote ntial 
i m m u ne res p o nse a n d t o preser ve he patic f u ncti o n, pre d nis o ne  or e q ui vale nt c ortic oster oi d  
will  be a d mi nistere d  pr o p h ylacticall y starti n g 2  da ys pri or t o t he S B -3 1 8  i nf usi o n a n d will 
be ta pere d o ver a peri o d of a p pr o xi matel y 2 0 wee ks (see A p pe n di x 3 ). 
•  Re d ucti o n i n al b u mi n s y nt hesis ; this is n ot e x pecte d gi ve n t he s m all fracti o n ( < 1 %) of 
tra ns d uce d cells i n w hic h t he al b u mi n l oc us will be disr u pte d  (see Secti o n 1. 7 ), a n d has n ot 
bee n o bser ve d i n a ni mal st u dies  i n w hic h le vels of tra ns d ucti o n a n d alb u mi n l oc us 
disr u pti o n e xcee d e d  b y se veral f ol d t h ose e x pecte d i n h u ma ns . 
•  Off -tar get m o dificati o n at t he S M C H D 1 l oc us; t his is n ot e x pecte d gi ve n t hat n o off -tar get 
acti vit y has bee n o bser ve d at cli nicall y rel e va nt le vels of al b u mi n o n -tar get acti vit y i n 
h u ma n cells i n vitr o (see Secti o n 8. 1. 2 ). 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 7 1  of 8 6  
1 2 .3  
S afet y M o nit ori n g C o m mittee   
A n e xter nal  S M C  wit h a p pr o priate me dical a n d scie ntific e x pertise will ha ve o versi g ht of t he 
st u d y.  
T he S M C will be c o n ve ne d  after t he c o m pleti o n of eac h c o h ort t o ad vise  w het her  it is safe t o 
pr ocee d wit h t he ne xt d ose c o h ort , a n d t o pr o vi de rec o m me n dati o ns o n pe diatric d osin g  a n d 
e x pa nsi o n of a n y c o h ort . T he S M C ma y als o b e c o n ve ne d at a n y ti me if t here are e xcessi ve or 
u ne x pecte d t o xicities ass ociate d wi t h t he c o n d uct of t he pr ot oc ol. S pecificall y, t he S M C will be 
c o n ve ne d if t he f oll o wi n g occ urs:  
•  A n y o ne Gra de 3 or hi g h er  A E , or a n y t w o Gra d e 2 A E s i n t he sa me s yste m or ga n class 
t hat persist f or  m ore t h a n 2 wee ks wit h t hera p y, pr o vi de d  t hese A E s are n ot relate d t o t he 
pri mar y M P S I  dise ase or treat me nt of t he M P S I disease . 
•  S A E n ot relate d t o t he pri mar y M P S I diseas e   
•  Deat h of a s u bj ect . 
•  De vel o p me nt of a m ali g na nc y . 
T he S M C will t he n e val uate a ll data t o a d vise w het her  t he c ha n ges s h o ul d b e ma de t o t he st u d y or 
w het her  accr ual  a n d d osi n g s h o ul d be halt e d. I n a d diti o n, n o f urt her d osi n g of s u bjects will be 
perf or me d u ntil a s u bsta ntial a me n d me nt is s u b mitte d t o t he re g ulat or y a ut h orit y(ies) f or re vie w, 
a n d t he a me n d me nt h as bee n a p pr o ve d b y t he site I R B/I E C or e q ui val e nt . 
T he S M C ma y als o rec o m me n d c ha n ges t o t he e nr oll me nt of c o h orts b as e d o n c u m ulati ve a d ult 
a n d pe diatric safet y a n d effic ac y data fr o m t his a n d si milar o n g oi n g first-i n-h u ma n cli nical trials 
t hat are s p o ns ore d b y Sa n ga m o a n d t hat use  i n viv o r A A V 2/ 6-base d g e ne tra nsfer of Z F Ns. 
S pecificall y,  st u d y S B-9 1 3 -1 6 0 2 i n 
M P S II s u bjects uses i de ntical Z F Ns ( S B -4 7 1 7 1 a n d 
S B -4 7 8 9 8) as t he prese nt st u d y i n c o m bi nati o n wit h a differe nt d o n or c D N A (e nc o di n g i d ur o nate-
2 -s ulfatase) ( Cli nicaltrials. g o v N C T 0 3 0 4 1 3 2 4). Gi ve n t he si milarities of t he a p pr oac h es, rele va nt 
data fr o m st u d y S B -9 1 3 -1 6 0 2 a n d ot her tri als s p o ns ore d b y Sa n ga m o ma y b e s hare d wit h t he S M C 
t o e x pa n d t he cli nical e x perie nce, partic ularl y as it relates t o safet y a n d d ose, a n d s uc h data ca n be 
use d b y t he S M C t o i nf or m its rec o m me n dati o ns f or t he prese nt st u d y . 
W he n n o f urt h er e nr olli n g or d osi n g decisi o ns are re q uire d of t he S M C, t he S M C will n o l o n ger 
meet. Sa n ga m o will c o nti n ue t o re vie w s u bject safet y data o n a n o n g oi n g b asis.  
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 7 2  of 8 6  
1 3  
S T A TI S TI C A L A N A L Y SI S A N D D A T A A N A L Y SI S  
T he pri mar y o bjecti ve of t his st u d y is t o e val uate t he safet y a n d t olera bilit y of S B-3 1 8 . All 
statistical s u m maries will be descri pti ve i n nat ure (e. g., 
mea ns, sta n dar d de viati o ns, a n d 
perce nt a ges). All s u bjects w h o recei ve a n y p orti o n of t he S B -3 1 8  i nf usi o n will be i ncl u de d i n t he 
a nal yses, e v e n t h ose w h o wit h dra w pre mat urel y fr o m t he st u d y. All res ults will be prese nte d 
se parat el y f or eac h of t he S B-3 1 8  d ose le vels. All a nal yses, s u m maries , a n d listi n gs will be 
perf or me d usi n g S A S versi o n 9. 2 or later . 
1 3 . 1 
Deter mi n ati o n of S a m ple Size   
T his st u d y will e nr oll up t o 2 7  s u bjects (1 s u bject i n C o h ort 2 a n d 2  s u bjects i n eac h of t he ot her 6 
c o h orts wit h p ote ntial e nr oll me nt of  a p pr o xi matel y 2  a d diti o nal s u bjects i n a n y c o h ort).  
T he sa m ple size  f or t his st u d y was n ot base d o n statistical c o nsi derati o ns, b ut is c o nsi dere d 
s ufficie nt t o pr o vi de preli mi nar y assess me nts of t he safet y a n d t olera bilit y of S B -3 1 8 i n s u bjects 
wit h M P S I , as well as bi oc he mical c ha n g es rel ate d t o t he pat h o p h ysi ol o g y of M P S I.  Su bjects 
w h o pre mat urel y disc o nti n ue t he st u d y pri or t o t he 1 2 m o nt hs of st u d y f oll o w-u p (i.e., s u bjects 
w h o were e nr olle d b ut n ot d ose d, were l ost t o f oll o w-u p, or disc o nti n ue d pre mat urel y f or a n ot her 
reas o n) ma y b e re place d at t he discreti o n of Sa n ga m o. 
1 3 . 2 
St atistic al A n al ys es 
E fficac y a nal ys es will be descri pti ve a n d e x pl or at or y i n nat ure. C o nti n u o us varia bles will be 
s u m marize d b y mea ns, st a n dar d d e viati o ns, me dia ns, a n d ra n ges b y c o h ort. Cate g orical vari a bles 
will be s u m marize d wit h c o u nts a n d perce nta ges per cat e g or y b y c o h ort.  
1 3 .3  
A n al ysis of t he C o n d uct of t he St u d y  
E nr oll me nt, maj or pr ot oc ol vi olati o ns, a n d disc o nti n uati o ns fr o m t he st u d y will be s u m marize d b y 
treat me nt c o h ort. T he n u m ber of s u bjects w h o were e nr olle d, disc o nti n ue d, a n d c o m plete d t he 
st u d y will be s u m marize d. 
De m o gra p hic a n d b aseli ne c haract eristics, s uc h as a ge, se x, a n d race will be s u m marize d usi n g 
mea ns, sta n dar d d e viati o ns, me dia ns, a n d ra n g es f or c o nti n u o us varia bles, a n d pr o p orti o ns f or 
cate g oric al varia bl es. All s u m maries will be prese nte d o verall a n d b y tr eat me nt c o h ort . 
1 3. 4  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt of t his st u d y is t he  i nci de nce of treat me nt-e mer g e nt A E s (i ncl u di n g S A Es). 
A d diti o nal safet y e val u ati o ns will i ncl u de:  
•  R o uti ne he mat ol o g y, c he mistr y, a n d li ver f u ncti o n la b orat or y tests, vital si g ns, p h ysical 
e xa m, E C G, E C H O, a n d c o nc o mita nt me dicati o ns.  
•  M o nit ori n g of c hi meris m i n p ost -H S C T s u bjects.  
•  Cra nial ner ve e xa m a n d m uscl e stre n gt h testi n g.  
•  Serial A F P testi n g a n d M RI of li ver t o e val uat e f or li ver mass . 
Safet y assess me nt will be perf or me d  o n all s u bjects . All re p orte d A E s will be c o de d t o a sta n d ar d 
set of ter ms usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Med D R A) . 
Treat me nt -e mer ge nt a d v erse e ve nts will be s u m marize d o verall a n d b y treat me nt c o h ort. F or eac h 
s u bject, t he ma xi m u m re p orte d se verit y of eac h a d verse e ve nt will be use d i n t he s u m maries b y 
se verit y gra d e.  I n a d diti o n, all seri o us a d verse e v e nts a n d A Es relate d t o st u d y treat me nt will be 
s u m marize d.  

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 7 3  of 8 6  
La b orat or y data will be s u m marize d f or eac h ti me -p oi nt at w hic h s peci me ns are c ollect e d. C ha n ge -
fr o m-B aseli ne val ues m a y be calc ulat e d f or sel ect e d la b orat or y p ara m et ers. S hift -ta bles ( Cha n g e -
fr o m-B aseli ne relati ve t o t he n or mal ra n ge) ma y be c o nstr ucte d f or selecte d la b orat or y para meters.  
1 3 . 5 
Sec o n d ar y E n d p oi nt s 
T he f oll o wi n g are s ec o n d ar y e n d p oi nts f or t his st u d y:  
•  C ha n ge fr o m B aseli ne i n:  
o  I D U A acti vit y meas ure d i n bl o o d. 
o  T otal G A G, D S G A G, a n d H S G A G  le vels (e x presse d as rati o t o creati ni ne) meas ure d i n 
uri ne .  
o  M o nt hl y a n d a n n ualize d fre q ue n c y a n d d os e of Al d uraz y me ( or e q ui val e nt E R T). 
•  A A V 2/ 6 cleara nce me as ure d b y vect or ge n o mes i n plas ma, sali va, uri ne, st o ol, a n d se me n b y 
P C R . 
At eac h sa m pli n g ti me p oi nt, t he act ual val ue a n d t he c ha n ge fr o m baseli ne f or I D U A  acti vit y a n d 
G A G le v els i n uri ne will be s u m marize d usi n g descri pti ve statist ics a n d pl otte d o ver ti me b y 
treat me nt c o h ort. 
F or s u bjects w h o u n der g o E R T wit h dra wal, c h a n ges  fr o m pre- t o p ost- E R T wit h dra wal  i n t he 
fre q ue n c y a n d d ose of E R T i nf usi o ns will be e val uate d a n d s u m marize d usi n g m o nt hl y, q uarterl y, 
a n d a n n ualize d t otal d ose a n d n u m ber of i nf usi o ns. D urati o n of E R T wit h dra wal ma y  als o be 
a nal yze d.  
A A V 2/ 6 cle ara n ce m eas ure d b y  v ect or g e n o mes  i n t he differe nt s a m ples will be pl otte d o ver ti me 
b y treat me nt c o h ort.  
1 3 .6  
E x pl or at or y E n d p oi nts  
T he f oll o wi n g are e x pl or at or y e n d p oi n ts f or t his st u d y: 
•  C ha n ge fr o m Baseli ne i n:  
o  T otal G A G, D S G A G, a n d H S G A G le vels meas ure d i n tiss ues (i ncl u di n g bl o o d, li ver 
tiss ue, a n d C S F). 
o  Perce nta g e a n d d ura bilit y of g e ne m o dificati o n at t he al b u mi n l oc us i n li ver tiss ue o btai ne d 
at bi o ps y.  
o  F orce d vital ca p acit y  me as ure d b y P F Ts.   
o  Dista nce wal k e d meas ur e d b y 6 M W T . 
o  J R O M. 
o  M RI of li ver t o e val uate li ver a n d s plee n v ol u me.  
o  M RI of brai n a n d cer vical s pi ne t o e val uate cli nical s oft tiss ue a n d/ or b o ne . 
o  Ne ur oc o g niti ve a bilities b y W A SI -II, W P P SI -I V, or B SI D -III, a n d b y V A B S-II. 
o  E ye e xa m f or c or neal cl o u di n g a n d visi o n testi n g.  
o  Hist o pat h ol o gical e xa m of li ver tiss ue.  
o  I m m u ne res p o nse t o A A V 2/ 6, Z F Ns , a n d I D U A meas ure d i n ser u m.  
A nal ysis details f or t he e x pl orat or y e n d p oi nts will be pr o vi de d i n t he Sta tistical A nal ysis Pla n. 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 7 4  of 8 6  
1 4  
I N V E S TI G A T O R O B LI G A TI O N S 
T he Pri nci pal I n v esti gat or  will e ns ure t hat t he st u d y is c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, 
Declarati o n of Helsi n ki , I C H G ui deli nes f or G o o d Cli nical Practice ( E 6), a n d all re g ulat or y a n d 
i nstit uti o nal re q uire me nts, i ncl u di n g t h ose f or s u bject pri vac y, i nf or me d c o nse nt, I R B/I E C or 
e q ui vale nt  a p pr o val , a n d rec or d rete nti o n.  
1 4 . 1 
I nf or me d C o nse nt 
N o i n vesti gat or ma y i n v ol ve a h u ma n b ei n g as a s u bject i n researc h c o vere d b y t hese re g ulati o ns 
u nless t he i n vesti gat or h as o btai ne d t he le gall y effecti ve i nf or me d c o nse nt of t he s u bject or t he 
s u bject’s le gall y a ut h orize d re pres e ntati ve. A n i n vesti gat or s hall see k s u c h c o nse nt o nl y u n d er 
circ u msta nces t hat pr o vi de t he pr os pecti ve s u bject  s ufficie nt o p p ort u nit y t o c o nsi der w het her or 
n ot t o partici pate , a n d t hat mi ni mize t he p ossi bilit y of c oerci o n or u n d ue i nfl ue nce. T he 
i nf or mati o n t hat is gi ve n t o t he s u bject or t he re prese ntati ve s hall be i n la n g ua ge u n d ersta n da bl e 
t o t he s u bject or t he re prese ntati ve.  
Sa n ga m o  will pr o vi de t he Pri nci pal I n v esti gat or  wit h a te m plate f or t he c o nse nt f or m.  State a n d 
l ocal la ws a n d/ or i nstit uti o nal re q uire me nts ma y re q uire t he discl os ure of a d diti o nal i nf or mati o n 
i n t he i nf or me d co ns e nt. T he pr o p ose d c o nse n t f or m m ust be s u b mitte d t o Sa n ga m o  pri or t o 
s u b missi o n t o t he I R B/I E C or e q ui vale nt t o e ns ure t hat it meets Sa n ga m o  sta n dar ds f or c o nse nt 
f or ms. T he I R B/I E C or e q ui vale nt m ust a p pr o ve t he c o nse nt f or m. A c o p y of t he a p pr o ve d f or m 
m ust be s u b mitte d t o Sa n ga m o .  
Pri or t o t he i nitiati o n of a n y pr oce d ures relati n g t o t he st u d y, i nf or me d c o nse nt s hall be d oc u me nte d 
b y t he use of a writte n c o nse nt f or m a p pr o ve d b y t he I R B/I E C or e q ui vale nt a n d si g ne d a n d date d 
b y t he s u bject at t he ti me of c o nse nt. A c o p y of  t he si g ne d i nf or me d c o ns e nt will be gi ve n t o t he 
pers o n si g ni n g t he f or m. T he Pri nci pal I n v esti gat or  m ust kee p eac h s u bject’s si g ne d c o nse nt f or m 
o n file f or i ns pecti o n b y a re g ulat or y a ut h orit y at a n y ti me.  
1 4 . 2 
I nstit uti o n al Re vie w B o ar d/ Et hics C o m mittee a n d Bi o S afet y C o m mittee  
T his pr ot oc ol, i nf or me d c o nse nt d oc u me nt, a n d rele va nt s u bsta nti ve data are t o be s u b mitte d t o t he 
a p pr o priate I R B/I E C or e q ui vale nt a n d Bi o Safet y C o m mittee ( B S C) f or re vie w a n d a p pr o val 
bef o re t he i nitiati o n of t he st u d y. A me n d me nts t o t he pr ot oc ol will als o be s u b mitte d t o t he 
I R B/I E C or e q ui vale nt a n d B S C (as a p pr o priate) pri or t o i m ple me ntati o n of t he c ha n ge. A letter 
d oc u me nti n g t he I R B /I E C or e q ui vale nt a n d B S C a p pr o val  m ust be recei ve d b y Sa n ga m o  pri or t o 
i nitiati o n of t he st u d y.  
1 4 . 3 
Pr ot oc ol A me n d me nts  
A n y c ha n ges t o t his pr ot oc ol will be i nitiate d b y Sa n ga m o  i n writi n g as a pr ot oc ol a me n d me nt. 
T he a me n d me nt m ust be s u b mitte d t o t he  I R B/I E C or e q ui vale nt t o get her with a re vise d i nf or me d 
c o nse nt f or m, if a p plica ble. Writte n d oc u me nt ati o n of I R B/I E C or e q ui vale nt a p pr o val m ust be 
recei v e d bef ore t he a me n d me nt ma y ta ke effect. 
1 4 .4  
S u bject Pri v ac y  
S u bject me dical i nf or mati o n o btai ne d f or t he p ur p oses of t his trial is c o nfi de ntial, a n d discl os ure 
t o t hir d parties ot her t h a n t h ose n ote d bel o w is pr o hi bite d. U p o n t he s u bject’s re q uest a n d writte n 
per missi o n, me dical i nf or mati o n ma y be gi ve n t o t he s u bject’s  pers o nal p h ysicia n or ot her 
a p pr o priate me di cal pers o n nel res p o nsi ble f or t he s u bject’s welfare.  Data g e nerat e d f or t his st u d y 
m ust be a vaila ble f or i ns pecti o n o n re q uest t o re prese nt ati ves of t he  a p pr o priate re g ulat or y 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 7 5  of 8 6  
a ut h orities (e. g.,  F D A / M H R A or e q ui vale nt ), ot her nati o nal or l ocal healt h a ut h orities, Sa n ga m o, 
a n d t he ass ociat e d I R B/I E C or e q ui vale nt. 
Release of researc h res ults or data t hat re v eal s u bject na mes or ot h er i de ntifiers, s uc h as 
p h ot o gra p hs, a u di o , or vi de ota pes, m ust be carrie d o ut i n acc or da n ce wit h De part me nt of Healt h 
a n d H u ma n Ser vices Sta n dar ds f or Pri v ac y of I n di vi d ual Healt h i nf or mati o n, 4 5 C F R  1 6 4. 5 0 8. 
Writte n a ut h orizati o n m ust be o btai ne d fr o m t he s u bject a n d I R B/I E C or e q ui vale nt pri or t o release 
of s uc h i nf or mati o n. I de nt ifia ble s u bject data ma y n ot be use d f or p ur p oses of pr o m oti n g t he 
i n vesti gati o nal pr o d uct. 
1 4 .5  
Re p orti n g O bli g ati o ns  
Sa n ga m o , t he Sp o ns or of t his st u d y, is re q uire d t o re p ort t o t he re g ulat or y aut h orities ( e. g., 
F D A/ M H R A or e q ui val e nt ) a n n uall y o n t h e stat us of t he tri al. Stat us re p orts m ust be file d b y t he 
Pri nci pal I n v esti gat or wit h his/ her  I R B/I E C or e q ui vale nt o n a n a n n ual b asis.  
T he Pri nci pal I n v esti gat or is als o res p o nsi ble f or i nf or mi n g his/ her  I R B/I E C or e q ui vale nt of t he 
pr o gre ss of t he st u d y a n d f or o btai ni n g a n n ual I R B/I E C or e q ui vale nt re ne wal. T he I R B/I E C or 
e q ui vale nt  m ust be i nf or me d at t he ti me of c o m pleti o n of t he st u d y. T he Pri nci pal I n vesti gat or 
s h o ul d pr o vi de his/ her  I R B/I E C or e q ui vale nt (if re q uire d b y t he i nstit uti o n) wit h a s u m mar y of 
t he res ults of t he st u d y. 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 7 6  of 8 6  
1 5  
A D MI NI S T R A TI V E C O N SI D E R A TI O N S  
1 5 . 1 
St u d y D oc u me nt ati o n  
T he Pri nci pal I n vesti gat or a n d st u d y staff are res p o nsi ble f or mai ntai ni n g a c o m pre h e nsi ve a n d 
ce ntralize d fili n g s yste m c o ntai ni n g all st u d y -relate d d oc u me ntati o n. T hese files m ust be s uita ble 
f or i ns pecti o n b y Sa n g a m o  or re g ulat or y a ut h orities (e. g., F D A/ M H R A or e q ui vale nt ) at a n y ti me, 
a n d s h o ul d c o nsist of t he f oll o wi n g ele me nts:  
•  S u bject files c o ntai ni n g t he c o m plete d me dical r ec or ds, s u p p orti n g s o urce d oc u me ntati o n, 
electr o nic C R Fs , a n d t he I R B/I E C or e q ui vale nt a p pr o ve d I nf o r me d C o nse nt si g ne d b y 
s u bjects. 
•  St u d y files c o ntai ni n g all versi o n s of t he I R B/I E C or e q ui vale nt a p pr o ve d pr ot oc ol wit h all 
a me n d me nts, I R B/I E C or e q ui vale nt a p pr o ve d i nf or me d c o ns e nt f or ms, c o pies of all 
pre -st u d y d oc u me nt ati o n, F or m F D A 1 5 7 2, a n d all c orres p o n d e nce t o a n d fr o m t he 
I R B/I E C or e q ui val e nt a n d Sa n ga m o . 
T he Pri nci pal I n vesti gat or s h o ul d mai ntai n a list of a p pr o priatel y q ualifie d pers o ns w h o are 
dele gate d t o perf or m si g nifica nt st u d y -relate d st u di es. I n a d diti o n, t he Pri nci pal I n v esti gat or s h o ul d 
m ai ntai n a si g nat ure s heet t o d oc u me nt si g nat ures a n d i nitials of all pers o ns a ut h orize d t o ma ke 
e ntries a n d/ or c orrecti o ns o n t he s o urce d o c u me nts a n d electr o ni c C R F s. 
1 5 . 2 
Rec or d R ete nti o n  
T he Pri nci pal I n vesti gat or s hall retai n rec or ds re q uire d t o be mai ntai ne d u n d er t his part f or a p eri o d 
of 2 years f oll o wi n g t h e date a mar keti n g a p plicati o n is a p pr o ve d f or t he dr u g f or t h e i n dicati o n 
f or w hic h it is bei n g i n vesti gate d. If n o a p plicati o n is t o be file d or if t he a p plicati o n is n ot a p pr o ve d 
f or s uc h i ndic ati o n, t he Pri nci pal I n vesti gat or s h all retai n t hes e rec or ds u ntil 2  years after t h e 
i n vesti gati o n is disc o nti n ue d a n d t h e a p pr o priate re g ulat or y a ut h orit y (e. g, F D A/ M H R A or 
e q ui vale nt ) is n otifie d. St u d y rec or ds s hall b e k e pt f or at least 2 5 years or t h e ma xi m u m peri o d b y 
a p plica ble p olic y or re g ulati o n ( w hic he ver is greater). H o we v er, t hes e d oc u me nts s h o ul d b e 
retai ne d f or a l o n ger peri o d if re q uire d b y t he a p plica ble re g ulat or y re q uire me nts or b y a n 
a gree m e nt wit h Sa n ga m o . It is t he res p o nsi bilit y of Sa n ga m o  t o i nf or m t he Pri nci pal In v esti gat or 
as t o w he n t hese d o c u me nts n o l o n ger nee d t o be retai ne d.  
1 5 . 3 
C ase Re p ort F or ms  
T he Pri nci pal I n v esti gat or is res p o nsi ble f or t he q u alit y of t he data rec or de d o n t he C R F . T he data 
rec or de d s h o ul d be a c o m plete a n d acc urate acc o u nt of t he s u bject’s rec or d c ollecte d d uri n g t he 
st u d y. 
Cli nical data will be rec or de d o n C R Fs  pr o vi de d b y Sa n ga m o . All f or ms m us t be le gi ble a n d 
c o m plete. T he Pri nci pal I n v esti gat or m ust re v ie w all e ntries f or c o m plet e ness a n d c orrect n ess. 
W he n c ha n g es or c orrecti o ns are ma de o n a n y C R F , a n a u dit trail will be ge nerat e d t o rec or d d ate 
a n d ti me w he n a c ha n ge is ma de, w h o ma de t h e c h a n ge, a n d reas o n f or t he c ha n ge as n ee de d. T h e 
ori gi nal e ntr y s h o ul d n ot be o bsc ure d. 
T he Pri nci pal I n vesti gat or a grees t o c o m plete a n d si g n C R F s i n a ti mel y fas hi o n at t he e n d of t he 
st u d y, a n d t o m a ke t h e m a vaila ble t o t he S t u d y M o nit or f or f ull i ns pecti o n. I n a d diti o n, al l dat a 
q ueries s h o ul d be res ol ve d pr o m ptl y.  

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             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 7 7  of 8 6  
1 5 . 4 
Ter mi n ati o n of t he St u d y  
Sa n ga m o  retai ns t h e ri g ht t o ter mi nate t h e st u d y a n d re m o ve all t he st u d y m aterials fr o m t he st u d y 
site at a n y ti me a n d f or a n y reas o n . S pecific i nsta nces t hat ma y preci pitate s uc h ter mi nati o n are as 
f oll o ws: 
•  C o m pleti o n of t h e st u d y at a n i n vesti gati o nal site  
•  Pri nci pal I n v esti gat or wit h dra wal fr o m partici pati o n i n st u d y 
•  Ter mi nati o n of st u d y b y Sa n ga m o  
1 5 . 5 
St u d y M o nit ori n g  
Sa n ga m o , as Sp o ns or of t his st u d y, is res p o nsi ble t o re g ulat or y a ut h orities f or e ns uri n g t he pr o per 
c o n d uct of t he st u d y wit h re gar d t o  pr ot oc ol a d h ere nce a n d vali dit y of t he data rec or de d o n t h e 
C R F s prese nte d t o t he re g ulat or y a ut h orities. Sa n ga m o  has t heref ore ass i g ne d a Cli nical M o nit or 
a n d a Me dical M o nit or t o t his st u d y. T heir d uties are t o ai d t he Pri nci pal I n vesti gat or a n d, at t he 
sa me ti me, Sa n ga m o  i n t he 
mai nte na n ce of c o m plete, le gi ble, well-or ga nize d, a n d easil y 
retrie va bl e data. I n a d diti o n, a Sa n ga m o  St u d y M o nit or will e ns ure a n u n dersta n di n g of t he 
pr ot oc ol, re p orti n g r es p o nsi bilities, a n d t he vali dit y of t he data.   
I n di vi d ual st u d y sites will be m o nit ore d b y a Sa n ga m o  re prese ntati ve at a p pr o priate i nter vals t o 
ass ure satisf act or y c o nse nti n g pr ocess, data rec or di n g, a n d pr ot oc ol a d h ere nce. T o perf or m t heir 
r oles well, t he Sa n ga m o  m o nit ors m ust be gi ve n direct access t o pri mar y s u bject data (s o urce 
d oc u me nts) t hat s u p p ort data e ntere d o nt o t he C R F s. T he Pri nci pal In vesti gat or a n d staff are 
e x pecte d t o c o o perate a n d pr o vi de all rele va nt st u d y d oc u me ntati o n i n detail at eac h site visit o n 
re q uest f or re vie w. Eac h st u d y ce nter will als o b e r o uti nel y m o nit ore d b y tele p h o ne a n d/ or b y 
e mail t o kee p a breast of s u bject stat us a n d t o a ns w er q uesti o ns. 
Re g ulat or y a u t h orities, t he I R B/I E C or e q ui vale nt, a n d/ or Sa n ga m o ’s Cli nical Q ualit y Ass ur a nce 
gr o u p ma y re q uest access t o all s o urce d oc u me nts, C R F s, a n d ot her st u d y d oc u me ntati o n f or 
o n -site a u dit or i ns pecti o n. Direct access t o t hese d oc u m e nts m ust be g uara ntee d b y t he Pri nci pal 
In v esti gat or, w h o m ust pr o vi de s u p p ort at all ti mes f or t hese acti vities.  
T he Pri nci pal I n v esti gat or or desi g nat e d pers o n s h o ul d a gree, as a mi ni m u m re q uire m e nt, t o rec or d 
t he f oll o wi n g i nf or mati o n i n t he s u bject n otes: 
•  Pr ot oc ol i de ntificati o n n u m ber, brief descri pti o n , or title  of st u d y . 
•  Date a n d state m e nt t hat s u bject has gi ve n writte n i nf or me d c o ns e nt . 
•  All st u d y f oll o w -u p visit dates . 
•  A E  as descri be d i n Secti o n  1 0  of t his pr ot oc ol . 
E ntries i n t he s u bject n otes m ust c o ntai n t he si g nat ure or i nitials of t he pers o n ma ki n g t he e ntries.  
T he St u d y M o nit or will perf or m s o urce dat a verifi cati o n at eac h m o nit ori n g visit.  
1 5 . 6 
C o nfi de nti al I nf or m ati o n a n d P u blic ati o n  
All i nf or mati o n pr o vi de d b y Sa n ga m o  t o t he Pri nci pal I n vesti gat or a n d a n y data or res ults 
ge nerat e d i n t he perf or ma nce of t his cli nical trial are c o nsi dere d c o nfi de nti al a n d re mai n t he s ole 
pr o pert y of Sa n ga m o . T he Pri nci pal I n vesti gat or s hall mai ntai n t his i nf or mati o n i n c o nfi de nce a n d 

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            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 7 8  of 8 6  
use t his i nf or mati o n s olel y f or i n t he c o n d u ct of t h e st u d y u nless ot her wis e e x pressl y a gree d t o i n 
writi n g b y Sa n ga m o.  
T he Pri nci pal I n v esti gat or u n dersta n ds a n d a grees t hat Sa n ga m o s hall ha v e t he ri g ht t o use t he data 
or res ults ge nerate d i n t he perf or ma n ce of t he st u d y f or a n y p ur p ose, i ncl u di n g i n re gistrati o n 
d oc u me nts f or r e g ul at or y a ut h orities i n t he U. S. or a br oa d, or f or p u blic disse mi nati o n i n t he f or m 
of pa pers, a bstracts, p osters, or ot her i nf or mati o nal materials t o be prese nte d at scie ntific meeti n gs, 
or p u blis he d i n pr ofessi o nal j o ur nals, or as a  part of a n aca de mic t h esis. T he Pri nci pal I n vesti gat or 
f urt her u n dersta n ds a n d a grees t hat Sa n ga m o s hall ha ve t he ri g ht t o first p u blicati o n of t he data or 
res ults of t he st u d y, w hic h is i nte n de d t o be a j oi nt, m ulti -ce nter p u blicati o n of t he s t u d y res ults 
ma de b y Sa n ga m o  i n c o nj u ncti o n 
wit h t he Pri nci pal I n vesti gat ors fr o m all a p pr o priate 
i n vesti gati o nal sites c o ntri b uti n g data, a nal ysis, a n d c o m me nts. A ut h ors hi p of p u blicati o ns 
res ulti n g fr o m t his st u d y will be base d o n c ust o mar y sta n dar ds f or attri b uti o n of a ut h ors hi p ta ki ng 
i nt o c o nsi derati o n fact ors s uc h as si g nifica nce of c o ntri b uti o n t o t he desi g n of t he st u d y, a n al ysis 
a n d i nter pretati o n of t he data, a n d criti cal re vie w of t he p u blicati o n. S u bse q ue nt t o t he first 
p u blicati o n of t he st u d y res ults b y Sa n ga m o , t he Pri nci pa l I n v esti gat or ma y p u blis h t he Pri nci pal 
I n v esti gat or’s site s pecific data or res ults. If t he Pri nci pal I n v esti gat or wis hes t o p u blis h t he 
Pri nci pal I n vesti gat or’s site s pecific data or res ults, a c o p y of s uc h pr o p ose d p u blicati o ns, pa pers, 
a bstracts, or o t her writte n materials, or a n o utli ne of a n y pr o p ose d oral prese ntati o ns, s hall be 
s u b mitte d t o Sa n ga m o f or re vie w at least 6 0 d a ys pri or t o s u b missi o n of s u c h writte n mat erials f or 
p u blicati o n, or a n y pr o p ose d oral prese ntati o n. Sa n ga m o s hall ha ve t he ri ght t o re vie w a n d 
c o m me nt o n s uc h writte n material or o utli ne, a n d t o c o nfir m t he acc urac y of t he data descri be d 
t herei n b y c o m paris o n wit h t hat c ollecte d d uri n g t he c o urse of t his st u d y. I n a d diti o n, Sa n ga m o  
s hall ha ve t he ri g ht t o re q uire t he Pri nci pal I n v esti gat or t o, a n d Pri nci pal I n v esti gat or s hall, re m o ve 
s pecificall y i de ntifie d c o nfi de ntial i nf or mati o n of Sa n ga m o ( ot her t ha n t he data or res ults of t he 
st u d y) a n d/ or del a y t he pr o p ose d p u blicati o n f or a n a d diti o nal 6 0  da ys t o e na ble Sa n ga m o t o file 
pate nt a p plica ti o ns. 
1 5 . 7 
St u d y F u n di n g  
T he c osts necessar y t o p erf or m t he st u d y will be a gree d t o b y t he Pri nci pal In v esti gat or a n d/ or t he 
ma na ge me nt of t h e st u d y facilit y , a n d will be d oc u me nte d i n a se parate fi na ncial a gree me nt. All 
fi na ncial a gree me nts will be si g ne d b y t he Pri nci p al In v esti gat or a n d Sa n g a m o . 
 
 

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Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 7 9  of 8 6  
1 6  
R E F E R E N C E S  
E ur o pea n Me dici nes A ge nc y. Al d uraz y m e . 
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W hitela w E. S mc H D 1, c o ntai ni n g a str uct ural -
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Ve ys P, Ea pe n M, K urtz ber g J, R oc ha V. O utc o mes of tra ns pla ntati o n usi n g vari o us he mat o p oietic 
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ca uses 
faci osca p ul o h u meral 
m usc ular 
d ystr o p h y 
t y pe 
2. 
Nat 
Ge net. 
2 0 1 2 
Dec; 4 4( 1 2): 1 3 7 0 -4.  
Le o n g H S, C he n K, H u Y, Lee S, C or bi n J, Pa k usc h M, M ur p h y J M, M aje ws ki IJ, S m yt h G K, 
Ale xa n der 
W S, Hilt o n DJ, Ble witt 
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S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 8 0  of 8 6  
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R uijter 
GJ. 
Resi d ual 
α -L -i d ur o ni dase 
acti vit y 
i n 
fi br o blasts 
of 
mil d 
t o 
se vere 
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M ol Ge n e t 
Meta b. 2 0 1 5 Se p-
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Ta n g M, Li Y, Z ha n g X, De n g T, Z h o u Z, M a 
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D, Pr o c o pi o E, Fi u mara A, B or g o A, Fri g o A C, Scar pa M. Cli nical efficac y of e nz y m e re place me nt 
t hera p y i n pae di atric H u nter patie nts, a n i n de pe n de nt st u d y of 3. 5 years. Or p ha net J Rare Dis. 2 0 1 4 
Se p 1 8; 9: 1 2 9.  
Wat ki ns S, Ma dis o n J, Gallia n o M, Mi nc hi otti L, P ut na m F W. A nal b u mi ne mia: t hree cases 
res ulti n g fr o m differe nt p oi nt m utati o ns i n t he al b u mi n ge ne. Pr oc Natl Aca d Sci U S A. 1 9 9 4 Se p 
2 7; 9 1( 2 0): 9 4 1 7 -2 1.   

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
        
 
 
 
 
            Sa n ga m o T hera p e utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9   
 
 
 
 
Pa ge 8 1  of 8 6   
A P P E N DI X 1 : S C H E D U L E O F E V E N T S  
D a y
7
2
4
6
8
1 2
1 6
2 0
2 4
2 8 *
3 2 *
3 6
4 0 *
4 4 *
4 8
5 2 *
1 5
1 8
2 1
2 4
2 7
3 0
3 3
3 6
E O S §
( w/i n 3 
m o nt hs of 
Baseli n e)
( w/i n 2 1 
da ys pri or 
t o S B- 3 1 8 
i nf usi o n)
D a y 0
D a y 1 
( +/- 1 da y)
I nf or me d C o ns e nt
X
Me di c al Hist or y
X
C o n c o mit a nt Me di c ati o ns
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
I n cl usi o n/ Excl usi o n
X
D e m o gr a p hi cs
X
P h ysi c al Ex a mi n ati o n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vit al Si g ns ( a)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
A E Ass ess me nt
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
E R T A d mi nistr ati o n Lo g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
J R O M ( b)
X
X
X
X
X
X
X
X
N e u r ol o gi c C r a ni al N e r ve Ex a m a n d 
M us cl e Stre n gt h Testi n g of U p pe r 
Extre miti es ( b)
X
X
X
X
X
X
X
X
1 2- Le a d E C G
X
X
X
X
X
X
X
X
X
X
E C H O
X
X
X
X
X
C h est X-r a y
X
Pre g n a n c y Test (c)
X
X
X
X
X
X
X
X
X
X
X
Cli ni c al La bor at or y Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Li ve r P a n el ( d)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
M P S I Ge n e S e q u e n ci n g (f)
X
S N P A n al ysis (f)
X
Vi r al Lo a d
X
N e utr ali zi n g A nti bo di es t o A A V2/ 6 
X
C hi me ris m Ass a y ( g)
X
X
X
X
X
G A G Testi n g i n Uri n e
X ( h)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
I D U A/ G A G Testi n g i n Bl o o d (i)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ci rc ul ati n g A F P
X
X
X
X
X
X
X
X
X
X
X
Ve ct or Ge n o me P C R i n Pl as m a
X ( 1 2 hr p ost-
i nf usi o n)
Ve ct or Ge n o me P C R i n Pl as m a, S ali va, 
Uri n e, St o ol, a n d S e me n (j)
X
X
X
X
X
X
X
X
X
X
X
P F Ts ( b)
X
X
X
X
X
X
X
X
X
X ( e)
S c r e e ni n g 
( q)
B as eli n e 
( +/- 2 da ys)
H os pit al o r A c ut e 
C a r e Fa cilit y
P R O C E D U R E
( +/- 1 we e k)
( +/- 1 m o nt h)
E T V 
W e e k 
M o nt h 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
        
 
 
 
 
            Sa n ga m o T hera p e utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9   
 
 
 
 
Pa ge 8 2  of 8 6   
D a y
7
2
4
6
8
1 2
1 6
2 0
2 4
2 8 * 3 2 *
3 6
4 0 * 4 4 *
4 8
5 2 *
1 5
1 8
2 1
2 4
2 7
3 0
3 3
3 6
E O S §
( w/i n 3 
m o nt hs of 
Baseli n e)
( w/i n 2 1 da ys 
pri or t o S B-
3 1 8 i nf usi o n)
D a y 
0
D a y 
1
( +/- 1 
da y)
6 M W T ( b)
X
X
X
X
X
X
X
X
Vi s u al Ac uit y Te st & C o r n e al Cl o u di n g 
Ex a m
X
X
X
X
X
X
V A B S-II 
X
X
X
X
X
X
X
X
X
Ne u r o c o g niti ve A biliti e s Ass e ss m e nt 
X
Ne u r o c o g niti ve A biliti e s Te sti n g ( k)
X
X
X
X
X
X
X
X
M RI of Li ve r
X
X
X
X
X
X
X
X
M RI of B r ai n a n d C e r vi c al S pi n e (l)
X
X
X
X
X
A C T H Sti m ul ati o n ( C os y nt r o pi n) Te st 
( m)
X ( pri or t o 
pr e dnis o n e)
X
Li ve r Bi o ps y ( n)
X
X
X
L u m b a r P u n ct u re ( n)
X
X
X
I m m u n o g e ni cit y Ass a ys ( o)
X
X
X
X
X
X
X
X
P re d ni s o n e ( o r e q ui val e nt c o rti c ost e r oi d) 
A d mi ni st r ati o n ( p)
X
X
S B- 3 1 8 I nf u si o n
X
P R O C E D U R E
S cre e ni n g 
( q)
B as eli n e
H os pit al o r 
Ac ut e C a re 
Fa cilit y
W e e k
E T V
( +/- 2 da ys)
( +/- 1 wee k)
( +/- 1 m o nt h)
X
M o nt h
 
*  
Wee k 2 8, 3 2, 4 0, 4 4, a n d 5 2 st u d y visits ha ve assess me nts t hat d o n ot re q uire e val uati o n at t he cli nical site, a n d t heref ore 
ma y be c o n d ucte d re m ote l y. Bl o o d 
a n d uri ne sa m ples at t hese visits  ma y be c ollecte d b y a q ualifie d h o me healt h n urse . F or t hese st u d y visits, G A G testi n g i n uri ne ma y be wai v e d f or s u bjects 
w h o d o n ot resi de i n t he U. S. Assess me nts f or A Es, c o nc o mita nt me dicati o n s a n d E R T a d mi nistrati o n l o g ma y be c o n d ucte d re m otel y o ver t he p h o ne b y st u d y 
staff. 
§ 
St u d y s u bjects ma y partici p ate i n t h e L T F U St u d y after 1 2 m o nt hs of f oll o w -u p i n t his st u d y , i n w hic h case a n E O S visit ma y be c o n d ucte d a n y ti me after Wee k 5 2 b ut bef ore 
t h e ne xt sc he d ule d st u d y visit. St u d y partici pa nts w h o wis h t o e nr oll i n t he L T F U St u d y wit h less t ha n 1 2 m o nt hs of f oll o w -u p i n t his pri mar y st u d y  ma y be c o nsi dere d o n a 
case-b y -case basis at t h e j u d ge me nt of t he Pri n ci p al I n vesti g at or a n d after c o ns ultati o n wit h t he S p o ns or.  I n t h ese cases, t h e E O S visit ma y be c o n d ucte d at a n y ti me o n t his 
st u d y. 
a. 
Vital si g ns ( hei g ht , wei g ht, s yst olic/ diast olic bl o o d press ure, heart rate, res pirat or y rate, a n d te m perat ure ; f or fre q ue n c y, refer t o t he St u d y Refere nc e Ma n ual. 
b.  As per mitte d b y s u bject’s ca pacit y . 
c. 
Ser u m pre g na nc y test will be perf or me d at Scree ni n g  a n d Baseli ne visits . Uri ne  pre g na nc y test will be perf or me d o n t he  Da y 0 visit if > 7 da ys fr o m Baseli ne 
pre g na nc y test . Uri ne pre g na nc y tests will be perf or me d u ntil Wee k 4 8 or u ntil 3 c o nsec uti ve plas ma sa m ples are ne gati ve f or A A V 2/ 6 , w hic he v er occ urs  first. 
d.  Li ver pa n el d oes n ot nee d t o be  dra w n as a se parate sa m ple if  sa m ples f or Cli nical La b orat or y Tests  are o btai ne d at t he sa me visit.  

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
        
 
 
 
 
            Sa n ga m o T hera p e utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9   
 
 
 
 
Pa ge 8 3  of 8 6   
e. 
Li ver pa n el will be perf or me d t wice a wee k f or t he first 2 0 wee ks p ost -S B -3 1 8  i nf usi o n a n d ma y be re m ote l y. Bl o o d sa m ples will be dra w n 2-4 da ys a p art 
w he n p ossi ble, e xce pt f or t he first wee k w he n it will be dra w n o n t he Da y 1 a n d Da y 7 visits. Li ver f u ncti o n tests will s u bs e q ue ntl y be c o n d ucte d at all  i n dicate d 
st u d y visits. 
f. 
F or a d ult s u bjects (c o h orts 1 t hr o u g h 3), t he assa y will be perf or me d o n bl o o d or sali va sa m ples. F or p ost -tra ns pla nt s u bjects, t he assa y will be perf or me d o n 
sali va sa m ples o nl y. F or pe diatric s u bjects (c o h orts 4  t hr o u g h 7 ), sali va sa m ples are preferre d. 
g.  F or p ost -H S C T patie nts o nl y.  
h.  
D uri n g Scree ni n g, sa m ples f or G A G testi n g i n uri ne will be c ollecte d o n 3 se parate da ys, eac h c ollecti o n occ urri n g at least 7 da ys after t he pre vi o us . All sa m ples 
f or G A G testi n g i n t h e uri n e m ust be c ollecte d at least 7 da ys after E R T a d mi nistrati o n [ +/ -1 da y] b ut pri or t o t he ne xt E R T i nf usi o n.  
i. 
F or I D U A / G A G testi n g i n blo o d, sa m ples m ust be o btai ne d 7 da ys after E R T a d mi nistrati o n ( +/ - 1 da y) a n d pri or t o t he ne xt E R T i nf usi o n. G A G a n d I D U A  
le vels i n bl o o d will b ot h be meas ure d c o nc urre ntl y fr o m t he sa me bl o o d sa m ple. 
j. 
Eac h t y pe of sa m ple ( plas ma, sali va, uri ne, st o ol, se me n) will  be c ollecte d u ntil 3 c o nsec uti ve s peci me ns of t hat sa m ple t y pe are re p orte d as ne g ati ve or 
u n detecta ble f or vect or ge n o me. C ollecti o n of se me n sa m ples ma y be wai ve d f or male pe diatric s u bjects (c o h orts 4  t hr o u g h 7 ) at t he discreti o n of Pri n ci pal 
I n vesti gat or. 
k.  As per mitte d b y s u bject’s ca pacit y. Ne ur oc o g niti ve a bilities testi n g i n pe diatric s u bjects will be d o ne b y V A B S -II a n d b y W A SI-II, W P P SI-I V, or B SI D-III, 
as a p pr o priate base d o n  t he N e ur oc og niti ve A bilities A ssess me nt perf or me d at Scree ni n g. 
l. 
Baseli ne M RI of brai n a n d cer vical s pi ne ma y be o btai ne d at Scree ni n g (t o get her wit h M RI f or li ver) i nstea d of at Baseli ne at  t he discreti o n of t he Pri n ci pal 
I n vesti gat or. 
m.  S h o ul d pre d nis o ne or e q ui vale nt  c ortic oster oi d treat me nt be c o nti n ue d or re peate d d ue t o i ncrease d tra nsa mi nase acti vit y, t he A C T H sti m ulati o n test will be 
re p eate d at t he e n d of ta per. Vital si g ns s h o ul d be m o nit ore d a n d rec or de d e ver y h o ur d uri n g t he A C T H sti m ulati o n test.  
n.  U nless c o nt rai n dicate d b y a Pri nci pal I n vesti gat or or p h ysicia n. 
o.  
Ma y be w ai ve d f or pe diatric s u bjects (c o h orts 4  t hr o u g h 7 ) at t he discreti o n of t he Pri nci pal I n vesti gat or t o mi ni mize re q uire d bl o o d v ol u mes.  
p.  See A p pe n di x 3 . 
q.  F or s u bjects w h o are re -scree ni n g f or partici pati o n i n t he st u d y, assess me nts i ncl u di n g E C H O, c hest X -Ra y, P F Ts, a n d M RI of li ver a n d/ or brai n a n d cer vical 
s pi ne perf or me d f or t he S cree ni n g of a s u bject i n t he pre vi o us 6 m o nt hs ma y be use d f or e val uati o n of i ncl usi o n/e xcl usi o n criteria at t he j u d ge me nt of t he 
Pri n ci pal I n vesti gat or. F urt her, ge n etic mar ker a nal ysis i ncl u di n g S N P a nal ysis a n d M P S I se q ue nci n g will n ot be re p eate d as res ults of t hese assess me nts d o 
n ot c ha n ge o ver ti me . 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 8 4  of 8 6  
A P P E N DI X 2 : E R T WI T H D R A W A L S C H E D U L E O F E V E N T S  
P R O C E D U R E*
E R T 
Wit h dr a wal 
Visit ( a)
E R T Wit h dr a wal Foll o w-
Up Visit ( wit hi n 1 2 
we e ks of E R T 
wit h dr a wal) (c)
1
2
3
4
6
8
1 0
1 2
C o n c o mit a nt Me di c ati o ns
X
X
X
X
X
X
X
X
X
X
P h ysi c al Ex a mi n ati o n
X
X
Vit al Si g ns ( d)
X
X
A E Ass ess me nt
X
X
X
X
X
X
X
X
X
X
E R T A d mi nistr ati o n Lo g
X
X
X
X
X
X
X
X
X
X
Cli ni c al La bor at or y Tests
X
X
Li ve r P a n el (e)
X
X
X
X
X
X
X
X
X
X
G A G Testi n g i n Uri n e 
X
X
X
X
X
X
X
X
X
X
I D U A  / G A G Testi n g i n Bl o o d 
X
X ( g)
X
X ( g)
X
X
X
X
X
X
P F Ts (f)
X
X
6 M W T (f)
X
X
E R T Cli ni c al Ass ess me nt
X
E R T Wit h dr a wal Mo nit ori n g Visits We e k, 
+/- 2 da ys ( b)
 
*  
Assess me nts ass ociate d wit h E R T wit h dra wal t hat are d u plicate d at re g ular sc he d ule d st u d y visits s h o ul d be 
wai v e d if visits are c o m bi ne d (see A p pe n di x 1 ).  
a) E R T Wit h dra wal visit ma y occ ur at or at a n y ti me after t he Wee k 1 2 visit (refer t o Secti o n 1 1. 4 f or a d diti o nal 
g ui da n ce).  
b)  Wee kl y E R T Wit h dra wal M o nit ori n g visits 
will  ta ke place o n a wee kl y basis f or t he first 4 wee ks, a n d o n a 
bi wee kl y basis f or t he l ast 8 wee ks f oll o wi n g t he E R T Wit h dra wal visit u ntil t he E R T Wit h dra wal F oll o w -U p 
visit . E R T Wit h dra wal M o nit ori n g visits ha ve assess me nts t hat d o n ot re q uire e val uati o n at t he cli nical site, a n d 
ma y t heref ore be c o n d ucte d at h o me if t he s u bject is re m ote.  Bl o o d a n d uri ne sa m ples at t hese visits ma y be 
c ollecte d b y a q ualifie d h o me healt h n urse. Assess me nts f or A Es a n d c o nc o mita nt me dicati o ns ma y be c o n d ucte d 
b y st u d y staff o ver t he p h o ne.   
c) T he E R T Wit h dra wal F oll o w -U p visit ca n occ ur at a n y ti me u p t o 1 2  wee ks after E R T wit h dra wal at t he discreti o n 
of t he Pri n ci pal I n vesti gat or. E R T d oes n ot nee d t o be restarte d at t he e n d of t he E R T Wit h dra wal F oll o w -U p 
visit.  
d)  Vital si g ns ( w ei g ht, s yst olic/ diast olic bl o o d press ure, heart rate, res pirat or y rate, a n d t e m perat ure ; refer t o t he 
St u d y Refere n ce Ma n ual).  
e) Li ver pa n el d oes n ot nee d t o be dra w n as a se parate sa m ple if cli nical la b orat or y tests are o btai ne d at t he sa me 
visit.  
f)  As per mitte d b y s u bject’s ca pacit y.  
g ) Ma y be wai v e d f or pe diatric s u bjects (c o h orts 4  t hr o u g h 7 ) at t he discreti o n of t he Pri nci pal I n vesti gat or t o 
mi ni mize re q uire d bl o o d v ol u mes.   
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 8 5  of 8 6  
A P P E N DI X 3 : I M M U N O S U P P R E S SI O N R E GI M E N 
Wei g ht of 
S u bject ( k g)  
Or al Pre d nis o ne ( m g/ d a y)  
D a y -2 t o D a y 0  
Wee k 1  
 Wee k 2  
Wee k 3 -1 6  
Wee k 1 7 -1 9  
Wee k 2 0  
>  6 0  
6 0  
6 0  
3 0  
1 5  
5  
S T O P  
5 5  
6 0  
6 0  
3 0  
1 5  
5  
S T O P  
5 0  
5 0  
5 0  
2 5  
1 5  
5  
S T O P  
4 5  
4 5  
4 5  
2 5  
1 5  
5  
S T O P  
4 0  
4 0  
4 0  
2 0  
1 0  
5  
S T O P  
3 5  
3 5  
3 5  
2 0  
1 0  
5  
S T O P  
3 0  
3 0  
3 0  
1 5  
1 0  
5  
S T O P  
< 3 0  
1 m g/ k g  
1 m g/ k g  
0. 5 m g/ k g  
0. 2 5 m g/ k g  
0. 2 5 m g/ k g 
e ver y ot her da y  
S T O P  
 
Pre d nis o ne or e q ui vale nt c ortic oster oi d  re gi me n is c o m me nce d 2 da ys pri or t o Da y 0 of S B-3 1 8  
i nf usi o n a n d gi ve n o nce dail y u nless ot her wise st ate d . S u bject’s li ver f u ncti o n will be m o nit ore d 
t wice a wee k w hile o n pre d nis o ne or e q ui vale nt c ortic oster oi d . Bl o o d f or l i ver pa nel s hall be dra w n 
2 t o 4 da ys a part w he n p ossi ble, e xce pt f or t he first wee k w he n it will be dra w n o n t he Da y 1 a n d 
Da y 7 visits.  Ta peri n g of pre d nis o ne or e q ui vale nt c ortic oster oi d  will o nl y pr ocee d if A L T/ A S T 
acti vit y le vels are sta bl e or decli ni n g ( base d o n t h e 2 assess me nts of t he prece di n g w ee k).  
If s u bjects de vel o p i ncrease d A L T > 2 f ol d B aseli ne w hile o n pre d nis o ne or e q ui vale nt 
c ortic oster oi d or after st o p pi n g pre d nis o ne or e q ui vale nt c ortic oster oi d , t he pre d nis o ne or 
e q ui vale nt c ortic oster oi d  re gi me n ma y be a dj uste d or rest arte d at t h e Pri nci pal I n vesti gat or’s 
discreti o n  after c o ns ultati o n wit h t he Me dical M o nit or.  
T wice a w ee k  li ver pa n el testi n g s h o ul d c o nti n ue u ntil t he pre d nis o ne or e q ui vale nt c ortic oster oi d  
c o urse has b ee n ter mi nate d.  
A n A C T H sti m ulati o n (c os y ntr o pi n) test will be perf or m e d pri or t o t he first pre d nis o ne or 
e q ui vale nt c ortic oster oi d  d ose a n d a gai n d uri n g Wee k 2 0 or at t he e n d of t he sc he d ule d ta per t o 
e ns ure t h at t he a dre n al c ortical f u ncti o n has n ot b ee n s u p press e d. S h o ul d pre d nis o ne or e q ui vale nt 
c ortic oster oi d  treat me nt b e re peat e d d ue t o i ncrease d tra nsa mi nase acti vit y, t he A C T H sti m ulati o n 
test will be re peat e d at t he e n d of ta p er at t he Pri n ci pal I n vesti gat or’s discreti o n. 
 
 

S B -3 1 8 -1 5 0 2  
 
 
 
 
 
 
 
            Sa n ga m o T hera pe utics, I nc.  
Cli nical St u d y Pr ot oc ol  
 
 
 
 
 
 
 
             C O N FI D E N TI A L  
A me n d me nt 7 1 2 D E C 2 0 1 9  
 
Pa ge 8 6  of 8 6  
A P P E N DI X 4 : I N S T R U C TI O N F O R LI V E R BI O P S Y S A M P L E C O L L E C TI O N A N D 
TI S S U E P R E P A R A TI O N  
S B -3 1 8 uses Z F N -ge ne s pecific tar gete d i nserti o n of a hI D U A  d o n or tr a ns ge ne i nt o t he li ver 
al b u mi n ge n o me l oc us i n s u bjects wit h M P S II t o pr o vi de l o n g -ter m pr o d ucti o n of hI DU A . T o 
deter mi ne t he efficie nc y of S B -3 1 8 , li ver tiss ue will be o btai ne d b y li ver bi o ps y f or a n al ysis b y 
hist o pat h ol o gic e xa mi nati o n, testi n g f or G A G le vels, a n d site s pecific m ol ec ular a nal ysis at t he 
al b u mi n l oc us. A F P le vels will be m o nit ore d t hr o u g h o ut t he st u d y, a n d a b n or mal res ults will be 
i n vesti gate d b y cli nical e val uati o n a n d M RI. A n y s u bject w h o h as a n el e vat e d A F P a n d/or  a n M RI 
mass s us pici o us f or H C C or greater t ha n 2 c m will u n der g o li ver bi o ps y. Hist o pat h ol o gic 
e xa mi nati o n a n d i nte grati o n site a nal ysis will b e perf or me d t o d eter mi ne t he ori gi n a n d nat ure of 
t he t u m or. 
Li ver Bi o ps y Sa m ple C ollecti o n a n d Tiss ue Pre parati o n  
Li ver bi o ps y will be o bt ai ne d at sele cte d visits u nl ess c o ntrai n dicate d b y a Pri n ci pal I n vesti gat or 
or p h ysicia n. T he li ver bi o ps y s h o ul d be di vi de d i nt o 3  sa m ples w he n p ossi ble. O ne li ver bi o ps y 
sa m ple will be c ollecte d i n 1 0 % ne utral b uffere d f or mali n a n d pr ocesse d f or hist o pat h ol o gical 
e val uati o n. T w o  li ver bi o ps y sa m ples will be flas h fr oze n i n li q ui d nitr o ge n.  Sa m ples ma y be 
st ore d i n a -8 0  º C freezer bef ore s hi p me nt. T he wei g ht of li ver tiss ue o btai ne d fr o m eac h bi o ps y 
sa m ple will be f or war de d t o Sa n ga m o.  
T he effi cie nc y of S B -3 1 8 i n tar geti n g i nserti o n of hI D U A d o n or tra ns ge ne t o t he li ver will be 
meas ure d b y site s pecific m olec ular a n al ysis of i nte gra ti o n e ve nts at t he al b u mi n l oc us.  
A d diti o nall y, t he fre q ue nc y of ot her ge n o mic m o dificati o n e ve nts li ke s mall i nserti o ns a n d 
deleti o ns (i n dels) will be deter mi ne d  b y Ne xt G e n erati o n Se q ue n ci n g ( N G S) at t he al b u mi n l oc us 
a n d at t he S M C H D 1 l oc us, t he o nl y k n o w n off -tar get site of S B-3 1 8 .  
I n a d diti o n, f or a n y s u bject w h o u n d er g oes li ver bi o ps y d ue t o a n el e vate d A F P a n d/ or a n M RI 
mass s us pici o us f or H C C, t he al b u mi n l oc us will be se q ue nce d b y N G S t o e xa mi ne t he ge n etic 
di versit y at t he al b u mi n Z F N clea v a ge s ite, w hic h ma y pr o vi de i nf or mati o n a b o ut t he cl o nal ori gi n 
o f t he s us pici o us mass.  A si n gle or li mite d n u m ber of m o difie d al b u mi n ge n ot y pes or A A V 
i nte grati o n sites w o ul d i n dicate t hat t he cells were deri ve d fr o m t he cl o n al e x pa nsi o n of m o difie d 
he pat oc yt es. A si milar se q ue nci n g a nal ysis will  als o be perf or me d o n t he S M C H D 1 l oc us t o 
e val uate t he g e netic di versit y at t he o nl y k n o w n off -tar g et site of S B-3 1 8 .