SIngle-Stage, Open-Label, Safety and Efficacy Study of Adeno-Associated Virus Encoding Human Aromatic L-Amino Acid Decarboxylase by Magnetic Resonance MR-guided Infusion Into Midbrain in Pediatric Patients With AADC Deficiency
Phase: PHASE1
Conditions: AADC Deficiency
Sponsor: Krzysztof Bankiewicz

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CLINICAL PROTOCOL 
 
 
A SINGLE-STAGE, ADAPTIVE, OPEN-LABEL, DOSE ESCALATION SAFETY STUDY OF 
ADENO-ASSOCIATED VIRUS ENCODING HUMAN AROMATIC L-AMINO ACID 
DECARBOXYLASE (AAV2-hAADC) ADMINISTERED BY 
MR-GUIDED CONVECTIVE INFUSION INTO THE MIDBRAIN IN 
PEDIATRIC PATIENTS WITH AADC DEFICIENCY 
 
 
IND Number: 16127 
 
 
 
Clinical Sites: 
 
University of California San Francisco 
 
The Ohio State University / Nationwide Children’s Hospital 

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TABLE OF CONTENTS 
 
1 
PROTOCOL SYNOPSIS ...................................................................................................................................................... 8 
2 
INTRODUCTION ............................................................................................................................................................ 15 
2.1 
SUPPORTING INFORMATION AND PRIOR CLINICAL EXPERIENCE .................................................................................................... 17 
2.1.1 
AADC Deficiency ........................................................................................................................................................ 17 
2.1.2 
Rationale for the Study .............................................................................................................................................. 17 
2.1.3 
Rationale for the Starting Dose and Infusion Volume ................................................................................................ 19 
3 
STUDY OBJECTIVES ....................................................................................................................................................... 21 
3.1 
PRIMARY ENDPOINTS .......................................................................................................................................................... 22 
3.2 
SECONDARY AND EXPLORATORY ENDPOINTS ............................................................................................................................ 22 
4 
STUDY DESIGN .............................................................................................................................................................. 22 
5 
SELECTION AND ENROLLMENT OF SUBJECTS ................................................................................................................. 24 
5.1 
INCLUSION CRITERIA ............................................................................................................................................................ 25 
5.2 
EXCLUSION CRITERIA ........................................................................................................................................................... 25 
6 
STUDY METHODS .......................................................................................................................................................... 26 
6.1 
RECRUITMENT .................................................................................................................................................................... 27 
6.2 
INFORMED CONSENT PROCEDURES ........................................................................................................................................ 27 
7 
STUDY RELATED TREATMENT AND PROCEDURES .......................................................................................................... 29 
7.1 
SCREENING PROCEDURES ..................................................................................................................................................... 29 
7.1.1 
Pre-screening questionnaire ...................................................................................................................................... 29 
7.1.2 
In-person Eligibility Screen (Day -90 to D-11) ............................................................................................................ 30 
7.2 
BASELINE ASSESSMENTS (D -10 TO D -1) ................................................................................................................................ 31 
7.3 
STUDY TREATMENT AND DOSING ........................................................................................................................................... 32 
7.3.1 
Investigational Drug .................................................................................................................................................. 33 
7.3.2 
Handling, Storage and Disposal of Drug ................................................................................................................... 34 
7.3.3 
Dosing and Dose Escalation ...................................................................................................................................... 34 
7.3.4 
Definition of Dose-limiting Toxicity ........................................................................................................................... 35 
7.4 
PROCEDURES FOR DELIVERY OF AAV2-HAADC ....................................................................................................................... 35 
7.4.1 
Preoperative Procedures ........................................................................................................................................... 35 
7.4.2 
CED and Imaging of Distribution ............................................................................................................................... 36 
7.4.3 
Infusion Procedure ..................................................................................................................................................... 36 
7.4.4 
Postoperative Procedures .......................................................................................................................................... 38 
7.4.5 
Discharge Criteria ...................................................................................................................................................... 38 
7.4.6 
Management of Post-therapy Dyskinesia ................................................................................................................. 39 
8 
SAFETY AND RESEARCH ASSESSMENTS ......................................................................................................................... 40 
8.1 
CLINICAL ASSESSMENTS ....................................................................................................................................................... 40 
8.1.1 
Adverse Event (AE) Log .............................................................................................................................................. 40 
8.1.2 
Medication Log .......................................................................................................................................................... 40 
8.1.3 
Behavior Diary ........................................................................................................................................................... 40 
8.1.4 
Medical and Neurologic Examinations ...................................................................................................................... 41 
8.2 
CSF, BLOOD AND URINE NEUROTRANSMITTER ANALYTES .......................................................................................................... 42 
8.2.1 
CSF Neurotransmitter Analytes ................................................................................................................................. 42 
8.2.2 
Plasma AADC and 3-O-Methyldopa Activity .............................................................................................................. 42 
8.2.3 
Urine vanillactate ...................................................................................................................................................... 42 

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8.3 
CLINICAL MEASURES ........................................................................................................................................................... 42 
8.3.1 
GMFM-88 .................................................................................................................................................................. 43 
8.3.2 
Pediatric Evaluation of Disability Inventory (PEDI) .................................................................................................... 43 
8.3.3 
Vineland Adaptive Behavior Scales-2nd edition ........................................................................................................ 44 
8.3.4 
Pediatric Quality of Life Inventory (PedsQL™) ........................................................................................................... 44 
8.3.5 
Patient/Caregiver Global Impression of Change (PGI-C) ........................................................................................... 44 
8.3.6 
Caregiver Priorities and child health Index of Life with Disabilities Questionnaire (CP Child) ................................... 44 
8.3.7 
Cognitive and Developmental Assessments .............................................................................................................. 44 
8.4 
NEUROIMAGING ................................................................................................................................................................. 45 
8.4.1 
MR-imaging ............................................................................................................................................................... 45 
8.4.2 
[18F]-FDOPA Positron Emission Tomography (PET) ................................................................................................... 45 
8.4.3 
DaTscan™ Ioflupane I-123 SPECT .............................................................................................................................. 46 
8.5 
HEMATOLOGY, CLINICAL CHEMISTRY AND IMMUNOLOGICAL ASSESSMENTS ................................................................................... 47 
9 
SCHEDULE OF STUDY ASSESSMENTS ............................................................................................................................. 48 
9.1 
PRE-SCREEN ...................................................................................................................................................................... 48 
9.2 
SCREENING (DAY -56 TO DAY -11) ........................................................................................................................................ 48 
9.3 
BASELINE (DAY -10 TO D -1) ................................................................................................................................................ 49 
9.4 
SURGICAL DELIVERY OF AAV2-HAADC – PRE SURGERY & SURGERY (DAY 0) ................................................................................ 49 
9.5 
HOSPITAL STAY (DAY 2) ....................................................................................................................................................... 50 
9.6 
TREATMENT FOLLOW-UP PHASE ............................................................................................................................................ 50 
9.6.1 
Visit 1 (day 10 +/- 4 days; at clinical site or clinic close to home) .............................................................................. 50 
9.6.2 
Visit 2-5 (day 28, 35, 42, 49 +/- 3 days - videoconference) ........................................................................................ 50 
9.6.3 
Visit 6 (day 56 +/- 3 days - videoconference) ............................................................................................................ 50 
9.6.4 
Visit 7 (Month 3 +/- 14 days) ..................................................................................................................................... 50 
9.6.5 
Visit 8 (Month 6 +/- 14 days) ..................................................................................................................................... 51 
9.6.6 
Visit 9 (Month 12+/- 14 days) .................................................................................................................................... 51 
9.6.7 
Visit 10 (Month 18+/- 14 days) .................................................................................................................................. 52 
9.6.8 
Visit 11 (Month 24+/- 14 days) .................................................................................................................................. 52 
9.6.9 
Visit 12 (Month 36 +/- 14 days) ................................................................................................................................. 52 
9.6.10 
Visit 13 (Month 48 +/- 14 days) ............................................................................................................................ 53 
9.6.11 
Visit 14 (Month 60 +/- 14 days) ............................................................................................................................ 53 
10 
MEDICATIONS FOR AADC DEFICIENCY ........................................................................................................................... 53 
11 
POST-MORTEM BRAIN EXAMINATION .......................................................................................................................... 54 
12 
SUBJECT WITHDRAWAL / DISCONTINUATION OF STUDY ............................................................................................... 54 
12.1 
VOLUNTARY PARTICIPATION ................................................................................................................................................. 54 
12.2 
DISCONTINUATION OF THE STUDY .......................................................................................................................................... 54 
13 
RISKS/DISCOMFORTS .................................................................................................................................................... 55 
13.1 
NEUROSURGICAL COMPLICATIONS ......................................................................................................................................... 55 
13.1.1 
Risks of Intra-cerebral Infusion ............................................................................................................................. 55 
13.1.2 
Risks of Gadoteridol Co-Infusion ........................................................................................................................... 56 
13.1.3 
Immediate Surgical Complications ........................................................................................................................ 57 
13.1.4 
Delayed Surgical Complications ............................................................................................................................ 58 
13.2 
IMMUNE RESPONSE, VECTOR AND GENE THERAPY RISKS ............................................................................................................ 58 
13.3 
RISKS OF IMAGING (MR IMAGING, PET) ................................................................................................................................. 59 
13.3.1 
Risks of MR imaging .............................................................................................................................................. 59 
13.3.2 
Risks of PET ........................................................................................................................................................... 60 
13.3.3 
Risks of DAT SPECT ................................................................................................................................................ 60 
13.4 
RISKS OF BLOOD SAMPLES .................................................................................................................................................... 61 

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13.5 
RISKS OF SEDATION ............................................................................................................................................................. 61 
13.6 
POST-THERAPY DYSKINESIA ................................................................................................................................................... 61 
13.7 
BEHAVIORAL ADVERSE EFFECTS ............................................................................................................................................. 62 
14 
SUBJECT SAFETY MONITORING ..................................................................................................................................... 62 
14.1 
TOXICITY CRITERIA .............................................................................................................................................................. 63 
14.2 
CRITERIA FOR INDIVIDUAL SUBJECT WITHDRAWAL .................................................................................................................... 63 
15 
OUTCOME MEASURES .................................................................................................................................................. 63 
15.1 
PRIMARY OUTCOME MEASURES ............................................................................................................................................ 63 
15.2 
SECONDARY OUTCOME MEASURES ........................................................................................................................................ 64 
16 
SAMPLE SIZE CALCULATIONS AND DATA ANALYSIS ....................................................................................................... 64 
16.1 
SAMPLE SIZE ...................................................................................................................................................................... 64 
16.2 
DATA ANALYSIS .................................................................................................................................................................. 64 
16.3 
SAFETY ANALYSIS ................................................................................................................................................................ 65 
16.4 
EFFICACY ANALYSIS ............................................................................................................................................................. 65 
17 
HUMAN SUBJECTS PROTECTION ................................................................................................................................... 66 
17.1 
HUMAN SUBJECTS INVOLVEMENT AND CHARACTERISTICS ........................................................................................................... 66 
17.2 
ADEQUACY OF PROTECTION AGAINST RISKS ............................................................................................................................. 67 
17.3 
SAFEGUARDS FOR VULNERABLE POPULATIONS .......................................................................................................................... 67 
18 
ANTICIPATED BENEFITS ................................................................................................................................................ 69 
18.1 
POTENTIAL BENEFITS TO SUBJECTS AND OTHERS ....................................................................................................................... 69 
18.2 
IMPORTANCE OF THE KNOWLEDGE TO BE GAINED ..................................................................................................................... 69 
19 
CLASSIFICATION OF RISK ............................................................................................................................................... 69 
20 
CONSENT DOCUMENTS AND PROCESS .......................................................................................................................... 69 
21 
DATA AND SAFETY MONITORING ................................................................................................................................. 70 
21.1 
DATA AND SAFETY MONITORING BOARD, MEDICAL MONITOR AND ADVISORY COMMITTEE .............................................................. 70 
21.2 
DOSE LIMITING TOXICITY ..................................................................................................................................................... 72 
21.3 
STOPPING RULES ................................................................................................................................................................ 72 
22 
QUALITY ASSURANCE ................................................................................................................................................... 73 
23 
ADVERSE EVENT AND UNANTICIPATED PROBLEM REPORTING ..................................................................................... 73 
24 
ALTERNATIVES TO PARTICIPATION ............................................................................................................................... 73 
25 
CONFIDENTIALITY ......................................................................................................................................................... 73 
26 
CONFLICT OF INTEREST ................................................................................................................................................. 74 
27 
TECHNOLOGY TRANSFER .............................................................................................................................................. 74 
28 
RESEARCH AND TRAVEL COMPENSATION ..................................................................................................................... 74 
29 
REFERENCES ................................................................................................................................................................. 75 

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LIST OF FIGURES 
 
Figure 1:  Imaging results from healthy children and children with AADC deficiency .......... 19 
 
Figure 2: Flowchart for Study Treatment and Dose Escalation ............................................... 23 
 
Figure 3: Study Schedule ......................................................................................................... 27 
 
 
 
LIST OF TABLES 
 
Table 1: Common signs and symptoms in patients with AADC deficiency ........................................... 15 
 
Table 2:  Dose Justification and Scaling Factor ...................................................................................... 21 
 
Table 3: Grading of Post-therapy Dyskinesia ......................................................................................... 39 
 
 
 
 
APPENDICES 
 
Appendix 1: Schedule of Events 
Appendix 2: NCI CTCAE (version 4.0) link 
Appendix 3: Medical Neurogenetics Neurotransmitter Test Information 
Appendix 4: GMFM-88 
Appendix 5: PEDI-CAT 
Appendix 6: PedsQL 
Appendix 7: Symptom Diary 
Appendix 8: Medications Interfering with DaTscan 
Appendix 9: Guidelines for Management of Post-Therapy Dyskinesia 
Appendix 10: Video Exam Protocol 
Appendix 11: CP Child Questionnaire 

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LIST OF ABBREVIATIONS 
 
 
Abbreviation 
Definition 
3-OMD 
3-O-methyldopa 
5-HIAA 
5-Hydroxyindoleactic acid 
5-MTHF 
5-methyltetrahydrofolate 
AADC 
Aromatic L-amino acid decarboxylase 
AAV2 
Adeno-associated virus Type 2 
AC 
Advisory Committee 
AE 
Adverse event 
CED 
Convection-enhanced delivery 
CNS 
Central nervous system 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CUP 
Compassionate Use Program 
DAT 
Dopamine transporter 
DDC 
Dopa decarboxylase 
DLT 
Dose-limiting toxicity 
DSMB 
Data safety monitoring board 
DTPA 
Diethylenetriaminepentaacetate 
FDA 
Food and Drug Administration 
FLAIR 
Fluid attenuation inversion recovery 
GMFM 
Gross Motor Function Measure 
hAADC 
Human aromatic L-amino acid decarboxylase 
HVA 
Homovanillic acid 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 
IND 
Investigational New Drug Application 
INC 
Interventional Neurotherapy Center 
IRB 
Institutional Review Board 
IV 
Intravenous 
LP 
Lumbar puncture 

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Abbreviation 
Definition 
MAO 
Monoamine oxide 
MR 
Magnetic resonance 
MRI 
Magnetic resonance imaging 
nAb 
Neutralizing antibody(ies) 
NCI 
National Cancer Institute 
NHP 
Nonhuman primate 
NIH 
National Institutes of Health 
NORD 
National Organization for Rare Diseases 
PCR 
Polymerase chain reaction 
PD 
Parkinson’s disease 
PDMS-2 
Peabody Developmental Motor Scales 2nd   edition 
PEDI-CAT 
Pediatric Evaluation of Disability Inventory-Computer Adaptive Test 
PedsQL 
Pediatric Quality of Life Questionnaire 
PET 
Positron emission tomography 
PICU 
Pediatric Intensive Care Unit 
PLP 
Pyridoxal phosphate 
PND 
Pediatric Neurotransmitter Diseases 
SAEs 
Serious adverse events 
SCD 
Sequential compression device 
SNc 
Substantia nigra pars compacta 
SPECT 
Single-photon emission computed tomography 
UK 
United Kingdom 
USA 
United States of America 
vg 
Vector genomes 
VTA 
Ventral tegmental area 

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1 
PROTOCOL SYNOPSIS 
 
 
A Single-Stage, Adaptive, Open-Label Dose Escalation Safety Study of Adeno-Associated Virus 
Encoding Human Aromatic L-Amino Acid Decarboxylase (AAV2-hAADC) Administered by MR- 
guided Infusion into the Midbrain in Pediatric Patients with AADC Deficiency 
 
The AAV2-hAADC vector consists of an adeno-associated virus, serotype 2 (AAV2) containing 
human AADC complementary DNA (cDNA), human cytomegalovirus (CMV) promoter and 
3’UTR sequences. Study drug is provided in a sterile formulation of phosphate buffered saline with 
0.001% Pluronic acid (F-68). AAV2-hAADC is supplied in 0.5 mL aliquots as a suspension at a 
target concentration of 4.9 x 1012 vector genomes per mL. 
The vector and excipient for dilution will be supplied to the clinical site by the Clinical Vector 
Core, Children’s Hospital of Philadelphia. 
The parenchymal use of gadoteridol is off-label, and also part of this study. 
 
Phase 1. Given the extremely rare nature of the disease and limited number of subjects, this study 
will generate data for dose selection, evaluation of safety, and confirmatory evidence of efficacy. 
A single stage study will address dose selection and a future study will further evaluate safety and 
efficacy of the selected dose. 
 
The overall objective of this study is to determine the safety and efficacy of AAV2-hAADC 
delivered to the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in children 
with aromatic L-amino acid decarboxylase (AADC) deficiency. Specifically, the study will assess: 
• Safety, as measured by adverse events (AEs), safety laboratory tests, brain imaging, and the 
relationship of AEs to study/surgical procedures or to AAV2-hAADC. 
• Clinical responses to treatment with AAV2-hAADC. The primary clinical outcomes will 
reflect the predominant motor deficits of loss of motor function and dystonic movements. 
 
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare recessive genetic disorder in 
which mutations in the gene encoding the AADC enzyme lead to deficient synthesis of 
catecholamines (dopamine, norepinephrine, epinephrine) and serotonin. Over 100 cases have been 
identified worldwide since the original description of the disorder in 1990. Affected children suffer 
chronic and severe motor, cognitive, and behavioral disability. The most prominent neurological 
symptoms are motor: hypokinesia, hypotonia, oculogyric crises, involuntary movements and motor 
developmental delay. Additional symptoms include emotional lability, sleep disturbance, and 
hypotension. Because of the specific location of the metabolic block in this disorder (the conversion 
of levodopa to dopamine), motor symptoms do not respond to therapy with levodopa, in contrast 
STUDY TITLE 
INVESTIGATIONAL PRODUCT 
CLINICAL PHASE 
STUDY OBJECTIVES 
STUDY RATIONALE 

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to the positive response observed in Parkinson's disease and in other inborn errors of dopamine 
metabolism. Most patients with AADC deficiency derive little or no benefit from currently 
available medical therapies. 
In recent years, use of a viral vector, adeno-associated virus type 2 (AAV2), encoding the human 
AADC gene (hAADC), has been developed for the treatment of Parkinson’s disease. Early studies 
have demonstrated that the gene can be safely delivered to the striatum in human subjects via 
targeted infusion. The current protocol proposes to adopt a similar strategy to deliver AAV2- 
AADC to select midbrain regions to treat AADC deficiency in pediatric patients. 
 
Male and female patients aged 4 and up years with a confirmed diagnosis of AADC deficiency 
who, in the Investigator’s opinion, are candidates for surgical therapy and who meet all 
inclusion/exclusion criteria, will be enrolled. 
The initial patients screened for this study will be those with severe motor impairment and motor 
developmental delay despite treatment with currently available medications. The selection of 
patients who have failed to benefit from existing treatments will exclude newly diagnosed patients, 
as it would take at least 12 months to evaluate response to medications and determine lack of motor 
benefit. 
For the first group of 3 subjects (Group 1), the primary goal is to assess procedural safety. The 
minimum age for the first group of patients will be 5 years. The selection of this lower age limit is 
intended to minimize the risks because response to standard therapy is less certain in younger 
children, and there are increased risks associated with skull fixation in very young children. Based 
on previous clinical experience in the treatment of neurotransmitter disorders, younger patients may 
have the potential to benefit the most from AADC gene transfer. Thus, the Investigator contacted 
the Agency after treating Cohort 1 to amend the clinical protocol and enroll subjects as young as 4 
years old. Although it is anticipated that younger patients may have greater potential than older 
patients to benefit from AADC gene transfer, there is no specific evidence that older patients would 
not also benefit. 
 
Inclusion Criteria 
1. Definite diagnosis of AADC deficiency, confirmed by at least two of the following three 
criteria: (1) CSF neurotransmitter profile demonstrating reduced HVA and 5-HIAA, and 
elevated 3-OMD concentrations, (2) plasma AADC activity less than or equal to 5 
pmol/min/mL, (3) molecular genetic confirmation of homozygous or compound 
heterozygous mutations in DDC. 
2. Age 4 years and up. 
3. Failed to derive adequate benefit from standard medical therapy (dopamine agonists, 
monoamine oxidase inhibitor, pyridoxine or related form of Vitamin B6). 
4. Unable to ambulate independently (with or without assistive device) 
5. Cranium sufficiently developed, with sutures closed, to enable surgical placement of 
SmartFrame®   system on the skull for MRI-guided stereotactic targeting. 
STUDY POPULATION 
INCLUSION/EXCLUSION CRITERIA 

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6. Brain MRI does not show any conditions or malformations that are clinically significant 
with respect to risks for stereotactic brain surgery. 
7. Parent(s)/guardian(s) of the study subject must agree to comply with the requirements of 
the study, including the need for frequent and prolonged follow-up. 
8. Both parents (or legal guardians) must give their consent for their child’s participation in 
the study. 
9. Stable medication regimen for treatment of AADC deficiency: no new medications 
introduced for at least 6 months, and no existing medication dose changes for at least 3 
months prior to Baseline. 
10. Baseline hematology, chemistry, and coagulation values within the normal pediatric 
laboratory value ranges, unless in the Investigator’s judgment, the out of range values are 
not clinically significant with respect to subject suitability for surgery. 
 
Exclusion Criteria 
1. Intracranial neoplasm or any significant structural brain abnormality or lesion (e.g., severe 
brain atrophy, white matter degenerative changes), which, in the opinion of the clinical 
investigators, would confer excessive risk and/or inadequate potential for benefit. 
2. Presence of other significant medical or neurological conditions that would create an 
unacceptable operative or anesthetic risk (including congenital heart disease, respiratory 
disease with daytime home oxygen requirement, prior history of serious anesthesia 
complications during elective procedures, history of cardiorespiratory arrest), liver or renal 
failure, malignancy, or HIV positive. 
3. Previous stereotactic neurosurgery. 
4. Coagulopathy, or need for ongoing anticoagulant therapy. 
5. Contraindication to sedation during surgery or imaging studies (FDOPA PET DAT SPECT, 
or MRI scans). 
6. Receipt of any investigational agent within 60 days prior to the Baseline and during study 
participation. 
7. Evidence of clinically active infection with adenovirus or herpes virus on physical 
examination. 
 
Safety: Assessment of AE or SAE and its relationship to study surgery, infusion, or treatment effect 
(graded as definite, probable, possible, unlikely or unrelated). 
• Adverse Events and Serious Adverse Events 
• Post-operative MRI and/or CT (with contrast if clinically indicated) 
• Clinical laboratory assessments (hematology, chemistry, immunology) 
Biological Activity: Demonstration of effective restoration of AADC function by assays of CSF 
neurotransmitter metabolites and F-DOPA PET imaging, as allowed by subject’s ability to travel 
PRIMARY ENDPOINTS 

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to undergo follow-up visits. 
 
To obtain preliminary data regarding the potential for clinical responses by assessing the magnitude 
and variability of changes in clinical outcome parameters. 
The principal clinical outcome measures are: 
• Motor function, as assessed by the Gross Motor Function Measure (GMFM-88) 
• Frequency of oculogyric episodes, as measured by a  Behavior Diary Secondary clinical 
outcome measures include: 
• Assessment of subject disability, as assessed using the Pediatric Evaluation of Disability 
Inventory (PEDI); adaptive behavior, as assessed using Vineland Adaptive Behavior Scale; 
Patient’s Global Impression of Change (PGI-C); and quality of life, as determined using the 
Pediatric Quality of Life Inventory (PedsQL). 
It is anticipated that the utility of established developmental and cognitive assessments may be 
limited because of the study population’s severe physical disability. Such developmental 
assessments include: 
• Peabody Developmental Motor Scales 2nd edition (PDMS-2) 
 
This study is an adaptive, single-stage dose-escalation, open-label safety study of AAV2-hAADC 
delivered by real-time image-guided convection-enhanced delivery bilaterally into the substantia 
nigra pars compacta and the ventral tegmental area of pediatric patients with AADC deficiency. 
There will be 31 subjects divided into 4 groups of up to 12 subjects each. The primary aim of this 
study is to determine the dose for future studies based on safety, biomarkers of pharmacological 
activity of AADC and clinical outcomes. 
Subjects will be enrolled sequentially into the first 2 dose groups, Group 1 followed by Group 2. 
Groups 3 and 4 will be enrolled in parallel after Group 2. 
 
 
SECONDARY & EXPLORATORY ENDPOINTS 
STUDY DESIGN 

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Group 1 will consist of three (3) subjects that meet the inclusion criteria will receive a single low 
dose of AAV2 hAADC (1.3 x 1011   vector genomes (vg), delivered as an infusate volume of up to 
160 μL of vector at concentration of 8.3´1011   vg/mL). The total AAV2-hAADC dose will be infused 
bilaterally via magnetic resonance (MR)-guided convective infusion into a total of up to 4 sites per 
subject in both the SNc and VTA (left and right). The infusate will be divided between the VTA 
and SNc (e.g., 30 µL into the VTA and 50 µL into the SNc). The inter-subject dosing interval will 
be no shorter than 90 days for the first 3 subjects. 
A Data and Safety Monitoring Board (DSMB) will be established to review safety data after each 
subject has been treated and will review the accumulated safety and efficacy data of Group 1. The 
DSMB report will be submitted to the FDA for review before Group 2 may commence. The DSMB 
will be notified of dose limiting toxicities (DLT) (see Dose-limiting Toxicity for definition) within 
5 business days of the initial report to the PI. If none of the first 3 subjects in Group 1 experiences 
a DLT that results in hospitalization beyond 90 days post-surgery, enrollment in Group 2 may 
commence. If 1 subject experiences a DLT, treatment of additional subjects will not proceed until 
review and approval of the DSMB. If 2 or more subjects experience a DLT, both treatment and 
enrollment will be stopped, pending DSMB review. The occurrence of serious safety problems may 
lead to discontinuation of further treatments, based on pre-determined Stopping Rules. 
The vector dose (volume and/or concentration) may be adjusted after the treatment of <3 subjects 
in Group 1 if the study team, DSMB, and study Advisory Committee determine, based on review 
of available data, that dose escalation or reduction is warranted. If dose escalation is warranted, 
total vg in Group 2 will be increased by factor of 3.1 (Table 2). Volume of infusion will remain 
constant between Group 1 and Group 2. Group 3 and 4 will receive the same vector concentration as 
Group 2 in 80-300 µL per hemisphere for coverage optimization of the target structures. 
The final analysis of the safety and clinical outcome assessments will be performed 1 year post- 
surgery. A follow-up analysis will be performed 2 years post-surgery. Thereafter, subjects will be 
followed long-term to assess safety and clinical status updates annually for up to 5 years following 
gene transfer. 
 
 
 
Subject recruitment will be conducted via 3 main sources: (1) collaboration with two foundations, 
the Pediatric Neurotransmitter Diseases (PND) Association (USA), and the AADC Research Trust 
(UK), which both maintain registries of children with AADC deficiency; (2) the International 
Working Group on Neurotransmitter Related Disorders (iNTD), a group of physicians who treat 
patients with AADC deficiency, and (3) notification about the trial through the following 
organizations and societies: the National Organization for Rare Diseases (NORD), Genetic 
Alliance, Child Neurology Society mailing list, ChildNeuro Listserve. Study information will be 
available on Clinicaltrials.gov and a study website. 
 
A total of up to thirty-one (31) subjects are planned to be enrolled and treated in this study 
 
Eligible subjects who have parental consent to be part of the clinical study must have screening 
evaluations and baseline functional testing over a period of up to three months prior to surgery. 
RECRUITMENT 
SUBJECT NUMBER 
TREATMENT DURATION 

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Subjects who at the time of surgery still meet all Eligibility Criteria will undergo surgery to deliver 
the gene vector in a single surgery. Given the nature of gene transfer, the duration of the treatment 
is expected to be life-long, hence we anticipate the need for a separate long-term follow-up study. 
 
Systematic clinical assessments will occur over a 24-month period postoperatively. Patients will be 
monitored for at least 5 years in a Long-Term Follow-up Study to the protocol. Permission for 
autopsy studies will be requested for all patients who die during the study. 
 
The dose levels chosen for this study are based on results obtained from analysis of a safety study 
in non-human primates, in which the clinical cannula and surgical procedure were used, as well as 
GMP-process-comparable AAV2-hAADC vector. Relevant volumes of anatomical target 
structures were used to provide planned dose levels in this study. Recent experience from an ethics 
committee (EC)-approved compassionate use of AAV2-AADC in AADC deficient children was 
started in Europe. This program has shown a good safety profile of higher doses and volume of 
infusion of AAV2-AADC in the AADC deficient population. 
 
All subjects who received study medication will be included in the analysis of the safety and 
efficacy data. 
Safety data will be summarized for the total study population and will be further broken down by 
the dose level. Treatment-emergent adverse events will be coded with the Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized by body system and preferred term. In addition, 
separate summaries will be provided for treatment-emergent adverse events by severity and 
relationship to study drug, as well as adverse events leading to study drug discontinuation and 
serious adverse events. The tolerability will be assessed by number of patients having DLTs and 
with premature discontinuations of study treatment. 
For the evaluation of efficacy, there will be two primary clinical outcome measures: 
• Motor Function, as assessed by the Gross Motor Function Measure (GMFM-88). The 
GMFM-88 total score will be used as the endpoint. The total score will be derived as an 
unweighted average of the 5-dimension scores: lying and rolling (17 items); sitting (20 
items); crawling and kneeling (14 items); standing (13 items) and walking, running, and 
jumping (24 items). Each dimension score will be defined as % of maximum score for the 
dimension in question. 
• Frequency of oculogyric episodes, as measured by a Behavior Diary: each recorded episode 
will be classified as mild, moderate or severe. The area under the curve (AUC) of the diary 
symptoms will be used as the endpoint. The AUC will be calculated for each study month 
as a sum of duration of symptoms (hours) multiplied by the severity (0-3) of the symptom 
in question. The endpoint is the change from baseline (average of 3 months preceding the 
baseline) to 1 year (average of 3 months preceding the visit at Month 12. 
All data collected during the study will be used for the evaluation of the primary clinical outcome 
measures. The evaluation will be focused on the following comparisons: 
DURATION OF FOLLOW-UP 
DOSE LEVEL (S) AND DOSE JUSTIFICATION 
DATA ANALYSIS PLAN 

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• Change from baseline to one year in all patients treated with the selected dose level (primary 
comparison). However, if no dose-response is seen at Stage 1 of the study, both dose levels 
will be included in the primary comparison. 
• Difference in change from baseline to one year between the patients treated with the selected 
dose level and the other dose level used. 
In addition to the comparisons defined above, efforts will be made to compare the changes seen in the 
present study to natural progression of the disease as assessed in The Natural History of Symptoms and 
Motor Function in the AADC Deficiency Study, a related external study at Washington University in St. 
Louis, led by Dr. Toni Pearson,. These comparisons may involve comparison of the changes between the 
treated patients from the present study and untreated patients, using endpoints derived from the elements 
of the primary outcome measures. The definition and analysis of these endpoints will depend on the 
availability of the data collected from The Natural History Study. 
 
A Medical Monitor with clinical expertise in pediatric movement disorders will be responsible for 
the review of all safety and adverse experience data. 
A Data Safety Monitoring Board, consisting of a minimum of 3 individuals with broad expertise 
in pediatrics, neurology, and gene transfer will be appointed. Dose-limiting toxicity will be 
defined as any Grade 3 or 4 toxicity (NCI CTCAE v.4) that is thought to be possibly or probably 
related to AAV2-hAADC. 
If none of the first 3 subjects experiences a Dose Limiting Toxicity (DLT) that results in 
hospitalization beyond 90 days post-surgery, more subjects may be enrolled. Should 2 or more 
subjects in either cohort experience DLT as defined above, the study will be stopped pending 
review and discussion with FDA. 
 
The occurrence of any of the following events (regardless of suspected causal associations) during 
or after the administration of AAV2-hAADC would result in the halting of study enrollment and 
notification of the DSMB, FDA, and IRB: 
• Any significant procedural deviation or violations, e.g. dosing error, equipment failure 
• Any symptomatic intra-cerebral hemorrhage or stroke that results in a significant new 
neurologic deficit that persists one month following surgery 
• Any central nervous system infections related to study interventions 
• Dyskinesias severe enough to require ICU admission for greater than 30 days 
• Any death 
Once a stopping rule is reached, the trial would be suspended (i.e., cessation of AAV2-hAADC 
administration to any subjects) pending a comprehensive safety review by the DSMB. Triggering 
of any Stopping Rule will prompt notification to FDA, IRB, NIH Office of Biotechnology, and the 
Institutional Biosafety Committee (IBC). 
Additional Stopping Rules may be developed if unexpected serious adverse events (SAE) with 
MEDICAL MONITOR AND DATA SAFETY MONITORING BOARD 
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likely related to AAV2-hAADC delivery, including delivery procedure, appear during the study. 
Events that do not clearly meet the above criteria may be submitted to the DSMB, at the discretion 
of the study investigators, for independent review. 
 
2 
INTRODUCTION 
 
Aromatic L-Amino Acid Decarboxylase (AADC) deficiency is an inborn error of neurotransmitter 
biosynthesis with an autosomal recessive inheritance. Affected children typically present in infancy with 
hypotonia, oculogyric episodes, dystonia and developmental delay, and suffer chronic and severe 
neurological dysfunction. Mutations in the gene encoding for the enzyme AADC lead to a combined 
deficiency of serotonin and catecholamines (dopamine, norepinephrine, and epinephrine). Since the 
initial description of the condition, over 100 patients with this disorder have been identified worldwide 
(Hyland and Clayton 1990) (Manegold et al. 2009; Brun et al. 2010). Despite the severity of the disease, 
many patients do survive to adolescence and young adulthood. Because the disease is caused by a 
profound loss of functional AADC, gene replacement is seen as one of the most desirable and potentially 
transformative candidate therapies. 
 
AADC deficiency causes motor, cognitive, and behavioral symptoms. The most prominent neurological 
symptoms are motor: hypokinesia, hypotonia, oculogyric crises, involuntary movements and motor 
developmental delay. Additional symptoms include emotional lability, sleep disturbance, and 
hypotension (Hyland and Clayton 1990; Hyland and Clayton 1992; Hyland et al. 1992; Swoboda et al. 
1999; Swoboda et al. 2003) (Lee et al. 2009) (Manegold et al. 2009); Table 1). 
Table 1: Common signs and symptoms in patients with AADC deficiency 
 
 
 
Symptom 
 
 
% 
 
All 
Patients 
 
Infancy 
≤18 mo 
 
Childhood 
≤18 mo 
Adoles- 
cence 
≥11 years 
 
 
Adulthood 
Hypotonia 
95 
74/78 
35/38 
33/33 
3/4 
3/3 
Oculogyric crises 
86 
67/78 
33/38 
28/33 
3/4 
3/3 
Sweating 
65 
51/78 
20/38 
26/33 
2/4 
3/3 
Developmental retardation 
63 
49/78 
22/38 
24/33 
1/4 
2/3 
Dystonia 
53 
41/78 
21/38 
16/33 
1/4 
2/3 
Hypertonia 
44 
35/78 
14/38 
18/33 
1/4 
2/3 
Feeding/swallowing difficulties 
42 
33/78 
17/38 
16/33 
0/4 
0/3 
Dysarthria/speech difficulties 
41 
32/78 
9/38 
20/33 
1/4 
2/3 
Hypersalivation 
41 
32/78 
12/38 
17/33 
1/4 
2/3 

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Ptosis 
39 
30/78 
18/38 
10/33 
2/4 
0/3 
Insomnia 
37 
29/78 
11/38 
17/33 
1/4 
0/3 
Irritability 
35 
27/78 
12/38 
12/33 
1/4 
2/3 
Hypokinesia 
32 
25/78 
8/38 
14/33 
1/4 
2/3 
Nasal congestion 
31 
24/78 
10/38 
12/33 
2/4 
0/3 
Temperature instability 
29 
23/78 
12/38 
9/33 
1/4 
1/3 
Poor head control 
28 
22/78 
10/38 
9/33 
2/4 
1/3 
Athetosis 
27 
20/78 
8/38 
11/33 
0/4 
1/3 
Poor eye fixation 
26 
19/78 
10/38 
9/33 
0/4 
0/3 
Chorea 
22 
17/78 
7/38 
9/33 
1/4 
0/3 
Brain Imaging: 
 
 
 
 
 
 
Abnormal MRI 
24 
19/78 
- 
- 
- 
- 
Abnormal EEG 
13 
10/78 
- 
- 
- 
- 
Abnormal CT 
6 
5/78 
- 
- 
- 
- 
 
A description of the clinical and biochemical features of AADC deficiency in 78 patients was published 
in 2010 (Brun et al. 2010) and features are tabulated in a public database (JAKE). (available at: 
www.biopku.org/BioPKU_DatabasesJAKE.asp). 
 
Current treatment strategies are limited, and in many cases not beneficial. Administration of the 
neurotransmitter precursors L-dopa and 5-hydrotryptophan is ineffective, as these precursors cannot be 
further metabolized to dopamine and serotonin without functional AADC. Therefore current therapies 
aim to correct neurotransmitter abnormalities by: 1) augmenting residual AADC activity with the 
cofactor of AADC, pyridoxine or pyridoxal phosphate (PLP); and 2) potentiating dopaminergic 
neurotransmission through the use of monoamine oxide (MAO) inhibitors and dopamine agonists. Of 
the 78 patients currently in the JAKE database, a positive response to therapy was observed in 15 
patients, with unsatisfactory or no response in the other 63 patients (Brun et al. 2010). 
 
In recent years, use of a gene therapy vector, adeno-associated virus Type 2 (AAV2), encoding the 
human AADC (hAADC) gene has been developed for the treatment of Parkinson’s disease. Early studies 
have demonstrated that the gene can be safely be delivered to the striatum via targeted infusion in adults 
with Parkinson's Disease (Christine et al. 2009) and in four children with AADC deficiency (Hwu et al. 
2012). 
 
The current protocol proposes to deliver the AAV2-hAADC vector to two specific regions of the 

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midbrain, substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), taking advantage of 
anterograde transport of AAV2 from these regions to deliver AAV2-hAADC to other brain regions 
important in the pathophysiology of the disease. By delivering AAV2-hAADC to the VTA and SNc of 
affected children, we postulate that we will substantially rescue dopamine biosynthesis. If successful, 
this therapy thus has the potential to improve motor function and the quality of life of patients with 
AADC deficiency. 
 
2.1 
Supporting Information and Prior Clinical Experience 
2.1.1 AADC Deficiency 
AAV2-hAADC gene therapy for patients with AADC deficiency is being investigated clinically at 
National Taiwan University Hospital, Taipei, Taiwan. In a compassionate treatment study, four (4) 
patients with AADC deficiency aged 4 to 6 years were treated with AAV2-hAADC that was delivered 
bilaterally to the putamen (1.5x10
11vg) (Hwu et al. 2012). The treatment protocol was based on the 
AAV2-hAADC studies in Parkinson’s disease (PD). All 4 patients in the published study were reported 
to tolerate the procedure without significant peri-operative complications. However, patients 
experienced transient dyskinesias (involuntary movements) as a result of putaminal AADC transduction, 
beginning approximately one (1) month after surgery. An additional 4 subjects, aged 2-9 years old, have 
been treated, with mean follow up for these 8 patients of 3.8 years (Hwu, Press Release, 2015). 
2.1.2 Rationale for the Study 
In the current study, AAV2-hAADC will be administered into the SNc and VTA of subjects with AADC 
deficiency. In contrast to PD, in which there is extensive degeneration of dopaminergic nigrostriatal 
neurons, DAT imaging reveals that the nigrostriatal pathway is largely intact in AADC deficiency (Dr. 
Wang-Tso Lee, Taiwan National Hospital, personal communication). By directly targeting the 
dopaminergic neurons that normally express AADC, we anticipate widespread distribution of AADC to 
their axon terminals within the caudate nucleus, putamen and nucleus accumbens. In addition, we have 
demonstrated in non-human primates that AAV2 vectors undergo anterograde transport. AAV2-hAADC 
delivered to the midbrain is expected to transport AADC via the nigrostriatal projection to axon terminals 
in the caudate nucleus and putamen (Johnston et al. 2009; Kells et al. 2012; Salegio et al. 2014). 
 
Although the SN/VTA is a smaller target as compared to the putamen for neurosurgical intervention, it 
is anticipated that broader distribution of AADC, achieved in a smaller delivery volume, has a greater 

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likelihood of achieving a better clinical outcome. In particular, it is our strong belief that restoring AADC 
in the dopaminergic axonal terminals results in a more physiologic endpoint than does expression of 
AADC in the post-synaptic striatal neurons, as is the case after putaminal delivery. Studies in transgenic 
dopamine-deficient mice with tyrosine hydroxylase deficiency demonstrate better motor outcomes when 
restoring tyrosine hydroxylase expression in midbrain dopaminergic neurons (Hnasko et al. 2006), than 
when tyrosine hydroxylase expression was induced in striatal neurons (Szczypka et al. 2001). 
 
In both mouse studies, hyperkinetic activity was observed after restoration of tyrosine hydroxylase 
expression. Hypersensitivity of postsynaptic dopamine receptors is postulated to be the mechanism 
underlying this hyperkinetic activity. A separate study in the same population of dopamine-deficient 
mice demonstrated reversibility of striatal dopamine receptor hypersensitivity after chronic L-dopa 
treatment (Kim et al. 2006), suggesting that receptor hypersensitivity responsible for hyperactivity would 
be corrected with the chronic restoration of dopamine production. 
The post-treatment hyperkinetic activity observed in mice is analogous to the involuntary movements 
(dyskinesias) observed in patients with congenital dopamine deficiency when levodopa treatment is 
initiated (Pons et al. 2013). In the proposed trial in patients with AADC deficiency, our aim is to restore 
dopamine production through gene transfer. We anticipate that treated subjects will develop dyskinesia 
after AAV2-hAADC delivery. Dyskinesia may emerge approximately one month after surgery, and 
eventually resolve as dopamine production stabilizes at the new, increased level leading to reduction of 
dopamine receptor hypersensitivity. If post-therapy dyskinesia does occur, we have a protocol for their 
assessment and management (see 7.4.6, Management of post-therapy dyskinesia). 

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Figure 1: Imaging results from healthy children and children with AADC deficiency 
 
All subjects will receive bilateral delivery of AAV2-hAADC. AADC-deficient patients do not display 
symptomatic asymmetry and no asymmetry is observed on structural or functional (PET) imaging (see 
Figure 1 provided by Dr. Lee, Taiwan National Hospital). 
Unilateral treatment carries the additional risk of causing motor dysfunction through asymmetry in the 
dopaminergic system that would be impossible to control with medications. A second negative feature 
of unilateral treatment would be the risk of inducing antibody formation to AAV2, precluding the 
effective treatment of the second side in a patient who obtains benefit from the unilateral infusion. 
Furthermore, there would be additional risks and challenges for the patients if a second neurosurgical 
procedure were required to treat the other side at a later time. 
2.1.3 Rationale for the Starting Dose and Infusion Volume 
The selection of the infusion volume and vector dose levels for the intended clinical study is based upon 
extensive non-clinical data, as well as prior and ongoing clinical studies. 
 
Overall brain volume reaches its maximum by the end of the first decade of life with gray matter 
structures developing in advance of that of the cerebral white matter. The brain of a child aged 7-11 years 
has completed 95% of its anticipated growth (Caviness et al. 1996). Cortical gray matter reaches its 

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maximum volume by 4 years of age whereas white matter volume continues to increase through the 
second decade of life (Pfefferbaum et al. 1994). The ratio of gray to white matter declines over time, 
reflecting both a reduction in gray matter and an increase of white matter volume beyond the first decade 
of life (Jernigan and Tallal 1990; Jernigan et al. 1991; Pfefferbaum et al. 1994). 
 
The volumes of the human ventral tegmental area (VTA), and SNc are 150 mm3   and 700 mm3   respectively 
(Eapen  et  al.  2011),  with  the  volume  of  the  SNc  being  140  mm3     (Ziegler  et  al.  2013).  In  order  to 
adequately cover the VTA, we will deliver 30 µL and 50 µL of AAV2-hAADC to the SNc. This 
calculation is based on data showing a ratio of 3:1 between the volume of vector infused into the NHP 
brain and the volume of AAV2-hAADC gene transfer (Su et al. 2010). Because the VTA is located 
adjacent to the midline, we reduced the volume of infusion to 30 µL in order to avoid leakage into the 
ventricular system. 
 
In a nonclinical safety study (S12-10383) in nonhuman primates (NHP), doses of 60 µL (30 
µL/hemisphere) of 5´1010   vg (8.3´1011   vg/mL) or 5´1011   vg (8.3´1012   vg/mL) were administered into the 
VTA/SN region without any adverse events. Because larger volumes of AAV2-hAADC vector could not 
be infused in this study (the vector would leak outside of the target area), a 60-µL infusion (30 µL per 
hemisphere) is the optimal volume. The corresponding structures in human children are 10-fold greater 
in volume. However, allowing for structural differences as well as clinical experience from our AAV2-
hAADC studies in Parkinson’s disease and the Taiwanese AADC deficiency study where a dose of 1.6 x 
1011   vg of AAV2hAADC was delivered (Hwu et al. 2012), the planned doses were adjusted to 
1.3 x 1011  vg (low dose) and 4.2 x 1011   vg (mid dose) in 160 µL (30 µL in the VTA and 50 µL in the SN 
on each side). The long-term safety study in NHP and results of a Phase 1 AAV2-hAADC clinical study 
in subjects with PD support the dose selection in the current clinical study. 
 
More recently, further delivery experience has been gained as AADC deficiency patients (n=11) have 
been treated in Europe (Poland) under an ethics committee (EC)-approved compassionate use program 
(CUP). In order to increase safety of the delivery, subjects treated under CUP received AAV2-AADC in 
a single-cannula insertion and using a higher volume (150 µL/side) and vector concentration (up to 
4.2x1012   vg/mL). The optimized procedure reduced was safe and well-tolerated by all subjects. Based on 
this evidence and in order to minimize the surgical risk, the vector for Groups 3 and 4 (ages 4-13 y and 
>13 y, respectively; n≤12 subjects per group) will be delivered at the same concentration used in Group 2 

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(2.6x1012   vg/mL) in a larger volume of up to 300 µL per side (for up to a total of 600 µL). The increased 
total volume of infusion is intended as a maximum volume, and termination of delivery will remain at 
the discretion of the operating neurosurgeon who will monitor distribution in real-time by intraoperative 
MRI. This vector dose is 2.8-fold lower than estimated human equivalent dose calculated for the highest 
dose tested in the GLP toxicology study in NHP (Table 2). 
 
Table 2: Dose Justification and Scaling Factor 
 
Study 
Group 
Volume 
(µL) 
Vector conc. 
(vg/mL) 
Dose 
(vg) 
HED 
(vg)* 
Non-Clinical Studies 
NHP GLP tox 
Low 
High 
60 
60 
8.3 x 1011 
8.3 x1012 
5.0 x1010 
5.0 x1011 
4.5 x1011 
4.5 x1012 
Clinical Studies 
First PD study 
Low 
Mid 
200 
200 
1.1 x1012 
3.7 x1012 
2.3 x1011 
7.5 x1011 
NA 
Current PD study 
Mid 
High 
900 
900 
8.3 x1011 
2.6 x1012 
7.5 x1011 
2.3 x1012 
NA 
Current AADC 
Deficiency CUP 
 
300 
4.2x1012 
1.3 x1012 
NA 
Proposed Clinical Study 
AADC Deficiency 
Low 
160 
8.3 x1011 
1.3 x1011 
NA 
 
Mid 
160 
2.6 x1012 
4.2 x1011 
NA 
 
High 
600 
2.6 x1012 
1.6 x1012 
NA 
* HED: Human Equivalent Dose is based on a 10-fold difference in brain volume between Cynomolgus monkey and a human 
child. 
 
3 
STUDY OBJECTIVES 
 
The overall objective of this study is to determine the safety and efficacy of AAV2-hAADC delivered 
to the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in children with aromatic 
L-amino acid decarboxylase (AADC) deficiency. Specifically, the study will assess: 
• Safety, as measured by adverse events (AEs), safety laboratory tests, brain imaging, and the 
relationship of AEs to study/surgical procedures or to AAV2-hAADC. 
• Biological activity of AADC, measured by assays of neurotransmitter metabolites and FDOPA 
PET imaging. 
• Clinical responses to treatment with AAV2-hAADC. The primary clinical outcomes will reflect 
the predominant motor deficits of loss of motor function and dystonic movements. 
 

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3.1 
Primary Endpoints 
Safety: Assessment of AE or SAE and its relationship to study surgery, infusion, or treatment effect 
(graded as definite, probable, possible, unlikely or unrelated). 
 
• Adverse Events and Serious Adverse Events 
• Post-operative MRI and/or CT (with contrast if clinically indicated) 
• Clinical laboratory assessments (hematology, chemistry, immunology) 
 
Biological Activity: Demonstration of effective restoration of AADC function by assays of CSF 
neurotransmitter metabolites and F-DOPA PET imaging. 
 
3.2 
Secondary and Exploratory Endpoints 
 
To obtain preliminary data for clinical response by assessing the magnitude and variability of changes 
in specific outcomes. 
The principal clinical outcome measures are: 
• Motor function, as assessed by the Gross Motor Function Measure (GMFM-88) 
• Frequency of oculogyric episodes, as measured by a Behavior Diary  
Secondary clinical outcome measures include: 
• Assessment of subject disability, as assessed using the Pediatric Evaluation of Disability 
Inventory (PEDI); adaptive behavior, as assessed using Vineland Adaptive Behavior Scale; 
Patient’s Global Impression of Change (PGI-C); and quality of life, as determined using the 
Pediatric Quality of Life Inventory (PedsQL) and caregiver’s priorities with the Caregiver 
Priorities and Child Health Index of Life with Disabilities (CP Child). 
Although we recognize that the utility of established developmental and cognitive assessments may be 
limited because of the study population’s severe physical disability, we will use the following: 
• Peabody Developmental Motor Scales 2nd edition (PDMS-2) 
 
4 
STUDY DESIGN 
 
This study is an adaptive, single-stage dose-escalation, open-label safety and efficacy study of AAV2- 
hAADC delivered by real-time image-guided convection-enhanced delivery bilaterally into the SNc and 

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VTA of pediatric patients with AADC deficiency. 
  
STUDY OVERVIEW 
 
  Aims: Assess safety and clinical efficacy; select optimal dose for future study 
 
 
 
 
* Up to 3 subjects will receive each dose. The vector dose may be adjusted after fewer than 3 subjects, at the 
discretion of the study team, DSMB, and steering committee, based on available safety and efficacy data. 
Stage 1 may therefore include more than 2 dose groups. 
 
Figure 2: Flowchart for Study Treatment and Dose Escalation 
 
There will be 31 subjects in this study. The primary aim is to determine the dose for future clinical trials 
based on safety, biomarkers, of pharmacological activity of AADC and clinical outcomes. 
 
The first 6 subjects will be enrolled sequentially into 2 dose groups, Group 1 followed by Group 2. 
Initially, up to 3 subjects initially will be enrolled in Group 1 and treated with a single dose of AAV2 
hAADC (1.3´1011    vg, delivered as an infusate volume of up to 160 μL of vector at concentration of 
8.3´1011 vg/mL) on Day 0. Enrollment in Group 2 may commence after the last subject in Group 1 is 
treated and followed through Month 3 post-surgery, with the approval of the data safety monitoring board 
(DSMB) and the FDA. If dose escalation is warranted, total vg in Group 2 will be increased by factor of 
3.1 (Table 2). Volume of infusion will remain constant between Group 1 and Group 2. 
 
The final safety and clinical outcome assessments will be performed 1 year post-surgery. A follow-up 
analysis will be performed for 5 years post-surgery to assess safety and clinical status updates. An 
overview of the study schedule on a per-subject basis is presented in Figure 3. 
 
Up to 24 additional subjects will receive a larger volume of infusion (up to a maximum of 300 µL) in 
each hemisphere to cover both VTA and SNc with a single cannula insertion (Table 3). Groups 3 and 4 
will be enrolled in parallel, will each include up to 12 subjects ages 4-13 years and >13 years, 
Group 1 (n=3*) 
• 
Dose 1 
• 
DSMB review of safety and biomarker 
(imaging, CSF neurochemistry) data after 
each subject is 3 months post-surgery 
• 
Determine dose for Group 2 
Group 2 (n=3*) 
• 
Dose 2 
• 
DSMB review of safety and biomarker 
(imaging, CSF neurochemistry) data after 
each subject is 3 months post-surgery. 
• 
Determine dose for further study 
 
DSMB review of safety and biomarker (imaging, CSF neurochemistry) data after 3rd subject in either 
Group 3 or 4 is 2 months post-surgery 
 
 
 

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respectively, and will receive the same vector concentration as Group 2. DSMB will review safety data 
after the 3rd subject (in either cohort) reaches 2 months post-surgery. By that time, it is likely the report 
will include safety data for 3 subjects followed for at least 2-3 months, which is the most meaningful 
period for detecting surgery and dose-related complications. 
 
Table 3:  Dose Groups 
 
 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
No. of Subjects 
N=3 
N=4 
N≤12 
N≤12 
Age (years) 
5-9 
4-6 
4-13 
>13 
Vector 
Concentration 
(vg/mL) 
 
8.3 x 1011 
 
2.6 x 1012 
 
2.6 x 1012 
 
2.6 x 1012 
Total Vg 
1.3 x 1011 
4.2 x 1011 
1.6 x 1012 
1.6 x 1012 
Total Volume 
of Infusion 
 
160 µL 
 
160 µL 
 
600 µL 
 
600 µL 
Cannula 
Insertions 
 
2 per side 
 
2 per side 
 
1-2 per side 
 
1-2 per side 
 
 
5 
SELECTION AND ENROLLMENT OF SUBJECTS 
 
We anticipate that the initial patients screened for this study will have severe motor impairment and 
motor developmental delay. Patients must also have tried currently available treatments without any 
obvious benefit. Because it would take at least 12 months to evaluate response to medications and 
determine lack of motor benefit, newly diagnosed patients will be excluded. 
 
For the first group of 3 patients, the primary goal is to assess procedural safety. The minimum age for 
the first group of patients will be 5 years. The selection of this lower age limit is intended to minimize 
the risks because response to standard therapy is less certain in younger children, and there are increased 
risks associated with skull fixation in very young children. Based on previous clinical experience in the 
treatment of neurotransmitter disorders, younger patients may ultimately have the potential to benefit the 
most from AADC gene transfer. Thus, the Investigator will contact the Agency after the first 3 subjects 
have been treated to discuss modifying the age requirement to enroll younger patients. Although it is 
anticipated that younger patients may have greater potential than older patients to benefit from AADC 
gene transfer, there is no evidence that older patients would not also benefit. 

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5.1 
Inclusion Criteria 
1. Definite diagnosis of AADC deficiency, confirmed by at least two of the following three 
criteria: (1) CSF neurotransmitter profile demonstrating reduced HVA and 5-HIAA, and 
elevated 3-OMD concentrations; (2) Plasma AADC activity less than or equal to 5 
pmol/min/mL; (3) Molecular genetic confirmation of homozygous or compound heterozygous 
mutations in DDC. 
2. Age 4 years and up. 
 
3. Failed to derive adequate benefit from standard medical therapy (dopamine agonists, 
monoamine oxidase inhibitor, pyridoxine or related form of Vitamin B6). 
 
4. Unable to ambulate independently (with or without assistive device). 
5. Cranium sufficiently developed, with sutures closed, to enable surgical placement of 
SmartFrame®   system on the skull for MRI-guided stereotactic targeting. 
 
6. Brain MRI does not show any conditions or malformations that are clinically significant with 
respect to risks for stereotactic brain surgery. 
 
7. Parent(s)/legal guardian(s) of the subject must agree to comply with the requirements of the 
study, including the need for frequent and prolonged follow-up. 
 
8. Parent(s)/legal guardian(s) with custody of subject must give their consent for subject to enroll 
in the study. 
 
9. Stable medication regimen for treatment of AADC deficiency: (i.e. no new medications 
introduced for at least 6 months, and no existing medication dose changes for at least 3 months 
prior to Baseline). 
 
10. Baseline hematology, chemistry, and coagulation values within the normal pediatric laboratory 
value ranges, unless in the Investigator’s judgment, the out of range values are not clinically 
significant with respect to subject’s suitability for surgery. 
5.2 
Exclusion Criteria 
11. Intracranial neoplasm or any structural brain abnormality or lesion (e.g., severe brain atrophy, 

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white matter degenerative changes), which, in the opinion of the study investigators, would 
confer excessive risk and/or inadequate potential for benefit. 
 
12. Presence of other significant medical or neurological conditions that would create an 
unacceptable operative or anesthetic risk (including congenital heart disease, respiratory 
disease with home oxygen requirement, history of serious anesthesia complications during 
previous elective procedures, history of cardiorespiratory arrest), liver or renal failure, 
malignancy, or HIV positive. 
 
13. Previous stereotactic neurosurgery. 
 
14. Coagulopathy, or need for ongoing anticoagulant therapy. 
 
15. Contraindication to sedation during surgery or imaging studies (SPECT, PET or MRI). 
 
16. Receipt of any investigational agent within 60 days prior to Baseline and during study 
participation. 
 
17. Evidence of clinically active infection with adenovirus or herpes virus on physical examination. 
 
6 
STUDY METHODS 
 
Subjects will be followed by a series of clinical assessments for a period of 2 years and undergo a long- 
term follow-up of annual visits up to 5 years from AAV2-hAADC administration (surgery date). 
Although not analyzed as part of the safety assessment portion of this study, patients will be screened 
yearly for up to five years after surgery. Scheduled visits are summarized in Schedule of Events 
(Appendix 1). An overview of the study schedule on a per-subject basis is presented in Figure 3. 
 

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Figure 3: Study Schedule 
 
6.1 
Recruitment 
Subject recruitment will be conducted through 3 main sources: (1) in collaboration with two foundations, 
the Pediatric Neurotransmitter Diseases (PND) Association (USA), and the AADC Research Trust (UK), 
which both maintain registries of children with AADC deficiency; (2) via the International Working 
Group on Neurotransmitter Related Disorders (iNTD), a group of physicians who treat patients with 
AADC deficiency; and (3) notification about the trial through the following organizations and societies: 
the National Organization for Rare Diseases (NORD), Genetic Alliance, Child Neurology Society 
mailing list, ChildNeuro Listserve. Details of the clinical protocol will be listed on the ClinicalTrials.gov 
website and on a study-specific website. 
 
6.2 
Informed Consent Procedures 
The proposed clinical research study is complex and requires a substantial time commitment from the 
subject and family. For this reason, the informed consent process will occur as a series of steps, through 
which families will learn about the rationale, objectives, and logistics of the trial. This will take place in a 
series of meetings with members of the study team over a number of weeks. The final study consent 
will be signed prior to the first trial-related procedure. The study investigators will ensure the subject’s 
parents/guardians: 
 
• understand the experimental nature of the intervention, 
*
M36
M48
M60
Visit 
12
Visit 
13
Visit 
14
Visit 
11
Visit 
10
Visit 
9
Visit 
8
Visit 
7
Visit 
6
Visit 2-5
*
*
*
*
*
M24
M18
M12
M6
M3
M2
M1
Visit 
1
D -90
D -10
SURGERY
BASELINE
STUDY TIMELINE
FDOPA PET•
Eligibility screen
(informed consent, MRI, 
FDOPA PET•, DaTscan•)
MRI, FDOPA 
PET•
•
Physical/Neurological Exam
Lumbar puncture
Motor function/QoL scales
if possible/needed
*

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• have a thorough understanding of the procedures and evaluations involved in the trial over a 
period of several years, 
• are aware of the potential risks, and 
• have realistic expectations, including the possibility that there will be no benefit. 
 
Anticipated steps in the process: 
 
1. Parent(s)/guardian(s) will acquire general information about the trial from a written summary 
made available through the recruitment channels outlined above. Or, if group information 
sessions are organized by parent-run foundations, study investigators will discuss the trial in more 
detail and be available to answer questions. 
 
2. During the pre-screening process, study investigators will meet with parent(s)/guardian(s) in 
person, or by telephone, for individual discussion. A preliminary discussion of risks and benefits 
will occur, and any specific concerns will be addressed. The time commitment required will be 
explicitly described. 
 
3. If the parent(s)/guardian(s) of the subject wish to proceed to the in-person screening stage, they 
will travel to meet in person with one of the study investigators at the beginning of the visit. The 
screening process and the study will be reviewed. Potential risks of the screening tests, operative 
procedure, and subsequent follow-up procedures will be described and reviewed in detail. The 
discussion will be documented by a written summary within 48 hours. 
 
4. Parent(s)/guardian(s) assessment. At this point, the parent(s)/guardian(s) understanding and 
expectations of study participation will be assessed, primarily to determine if they have realistic 
expectations of the potential risks and benefits to the subject. 
 
5. Following the screening procedures, if the subject is eligible for ongoing participation in the study, the 
parent(s)/guardian(s) will have a final discussion with a study investigator to determine their commitment 
to the next phase of the trial which includes the baseline assessments, the surgical procedure, and long-
term follow-up. If the parent(s)/guardian(s) agree, they will confirm their willingness to proceed by signing 
the informed consent document on the final page. The two-step process will assure they have an improved 
understanding of the risks and commitment to return for all follow-up visits over 60 months. A copy of 
the signed consent will be provided to the parent(s)/guardian(s) at each stage of the process and the original 
will be kept with study records. 

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7 
STUDY RELATED TREATMENT AND PROCEDURES 
 
7.1 
Screening Procedures 
7.1.1 Pre-screening questionnaire 
In the first stage of screening, the following information will be forwarded to the study investigators for 
review: 
 
• Documentation of the subject’s diagnosis of AADC deficiency with the presence of at least two 
of the following three criteria: 
 
1. CSF neurotransmitter metabolites demonstrating reduced HVA and 5-HIAA and 
elevated 3-OMD concentrations 
2. Plasma AADC activity less than or equal to 5 pmol/min/mL 
3. Molecular genetic confirmation of two homozygous or compound heterozygous 
mutations in DDC. 
 
• A detailed medical questionnaire regarding the subject’s course of symptoms directly related to 
AADC deficiency, current and past medications, other past medical and surgical history 
(especially as relevant to assessment of anesthetic risk), developmental history, and current level 
of function. 
• The subject’s medical records, and discharge summaries from all previous relevant hospital 
admissions. 
 
• Brain MRI images if available. A brain MRI will be performed for all subjects that progress to 
the in-person screening stage. 
 
• If eligibility criteria are met, a medication review will be performed to determine if any 
medications need to be tapered and/or discontinued prior to the in-person screening visit 
 
a. Medications that may interfere with DaTscan (refer to Appendix 8). DaTscan may be 
performed if, after reviewing the subject’s medical history and screening materials, the 
study clinical team deems necessary to assess the integrity of the subject’s nigrostriatal 
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b. Levodopa. (Exogenous levodopa would cause elevation of CSF 3-OMD beyond the level 
due to the primary disease, and confound post-operative measurements that will be relied 
upon to assess the effect of gene transfer) 
 
The study investigators will review the pre-screening information. If the subject is a candidate for 
advancement to the in-person eligibility screen, the study team will then arrange for subject travel to the 
center. 
 
7.1.2 In-person Eligibility Screen (Day -90 to D-11) 
Screening tests and procedures will be conducted at the study center over the course of 1-2 weeks: 
 
• 
 The parent(s)/legal guardian(s) of the subject will meet with one of the study investigators to 
review the consent form in detail. A visit with a social worker will be scheduled as part of the 
informed consent process. The consent form must be signed prior to any study procedures being 
performed. 
• Neurological and anesthesiology evaluation: The subject will be evaluated by the study 
neurologist. In addition, anesthesiology evaluation will be performed. Patients with AADC 
deficiency have an increased risk of hypoglycemia, hypotension, and bradycardia during periods 
of physiological stress due to peripheral catecholamine deficiency. Particular factors to be 
assessed include: 1) the appropriate protocol for pre-procedure fasting if the subject has any 
history of fasting hypoglycemia; 2) any history of symptomatic hypotension or bradycardia; 3) 
history of upper airway or respiratory complications. 
• A contrast brain MRI will be performed to examine brain anatomy, exclude any structural 
abnormalities that would make the subject ineligible, and for the purposes of neurosurgical 
planning. 
• An [18F]-FDOPA PET may be performed as a marker of baseline AADC activity if study team 
determines that additional data are required to confirm the diagnosis. In cases when it is not in 
the subject’s best interest to travel and undergo examination under anesthesia the PET scan 
might be not performed. 
• DaTscan™ Ioflupane I-123 SPECT imaging may be performed if after reviewing the 
subject’s medical history and screening materials the study clinical team deems necessary 
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• A lumbar puncture will be performed to obtain a sample of CSF for neurotransmitter analysis 
(baseline sample #1). The LP will be done with sedation if necessary and may be scheduled at 
the same time as the MRI. 
• Blood will be collected for plasma AADC activity, 3-O-Methyldopa, routine hematology and 
clinical chemistry, coagulation, and AAV nAb and AAV PCR analysis. 
• Urinalysis will be performed, and female subjects with reproductive capacity will have a urine 
pregnancy test. 
 
Data obtained during the Screening period will be reviewed by the study investigators. If at the end of 
the Screening period, the subject is eligible for inclusion in the study and his/her parent(s)/guardian(s) 
have provided consent, the caregivers will be instructed how to complete a behavior diary. The diary of 
motor and behavioral symptoms should be completed twice between the Screening and Baseline visits, 
each over a consecutive 7-day period at least 1 month apart. A log of the timing, duration, and severity 
of oculogyric crises will be maintained on an ongoing basis. 
 
Participation in the treatment component of the study will be confirmed with the parents/guardians by the 
study investigators prior to scheduling of the actual surgical procedure. The parents/guardians will 
confirm their consent to proceed by completing the final signature page of the informed consent 
document. 
 
7.2 
Baseline Assessments (D -10 to D -1) 
The subject and parent(s)/legal guardian(s) will meet with members of the study team for Baseline 
clinical evaluations within 10 days to 24 hours before study drug administration. The following tests 
and procedures will be performed: 
• The Investigator will review medications and the symptom diaries and perform a physical and 
neurological examination. 
• Motor function (Gross Motor Function Measure [GMFM]-88), cognitive, and developmental 
assessments will be performed. 
• Parent(s)/legal guardian(s) will complete the Pediatric Quality of Life Questionnaire (PedsQL), 
Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) and CP Child 
questionnaires and Vineland-II survey. 
• A second set of baseline blood, CSF, and urine samples will be collected for neurotransmitter 

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metabolite, AADC enzyme analysis and 3-O-Methyldopa on the day of surgery, following 
induction of anesthesia and prior to the start of the surgical procedure. A type and screen will be 
obtained at the discretion of the neurosurgeon. 
 
7.3 
Study Treatment and Dosing 
The surgical procedure to deliver the AAV2-hAADC vector will be performed in a magnetic resonance 
(MR)  suite  with  the  skull-mounted  SmartFrame®     and  ClearPoint®     targeting  system  (or  similar  FDA- 
approved system that allows for MR-controlled delivery of AAV2-hAADC vector). The procedure will 
be performed by a neurosurgeon experienced with MR-based stereotactic placement of MR-based 
delivery of therapeutics and/or DBS leads into the brain. Subjects will be secured in a head-frame and 
four target sites (bilateral SNc and VTA) will be located by MR images of the brain. 
 
For Groups 1 and 2, 80 µL of AAV2-hAADC will be delivered: 50 µL in SNc and 30 µL in VTA in 2 
separate cannula passes. Recently, 11 AADC deficient patients have been treated with the same vector 
in the Mazovian Bródnowski Hospital in Warsaw Poland under an EC-approved CUP. Under this 
program the first 5 subjects received the same amount of total vg as Group 2 (4.2 x 1011   vg), administered 
in a larger volume of infusion (150 µL) with a single-cannula insertion strategically positioned to cover 
both SNc and VTA in the same infusion. Subsequent patients (n=6) received the same volume of a 1.6- 
fold higher concentration than Group 2 (4.2x1012 vg/mL). The modification of the surgical delivery 
reduced the surgical risks (lower number of cannula insertions and associated risks, shorter surgical and 
anesthesia times) and demonstrated a favorable safety profile (no AE/SAE related to the study drug or 
surgical procedure) and was well-tolerated by all subjects. 
 
Based on this experience, and in order to improve the safety and reduce the procedure time, for Groups 
3 and 4 the operating neurosurgeon will plan to deliver the vector with the same cannula-insertion in 
each hemisphere aiming to cover both SNc and VTA in the same infusion. The cannula will be positioned 
in between both structures and a volume of up to 300 µL per side will be administered at a flow rate of 
1-15 µL/min. The use of 1 or more cannula insertions to cover the SNc and VTA on each hemisphere 
(i.e., 1 cannula insertion for SNc/VTA or 1 cannula insertion for SNc plus 1 cannula insertion for VTA) 
will remain at the discretion of the operating neurosurgeon on the day of surgery based on pre-surgery 
planning that considers individual subject variations in the anatomy of target sites and planned trajectory. 
To accommodate possible anatomical and trajectory needs, the Vi delivered in a single infusion will be 

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based on MR imaging of the infusate for up to 300 µL per side to cover SNc/VTA combined, or 
separately as in Groups 1 and 2. Near real-time monitoring of the infusion by MRI-contrast admix to the 
vector solution will allow the neurosurgeon to monitor the infusion, adjust the volume as needed and 
determine the final volume that is infused at each site based on best judgment for delivery to each 
SNc/VTA while minimizing off-target distribution. 
 
If significant backflow or distribution into non-targeted areas is observed at a particular cannula 
placement, the infusion at that site will be stopped and consideration will be given to moving the cannula 
to a new position within the SNc/VTA region of the midbrain. Likewise, if continued infusion at a 
particular cannula placement is not observed to be increasing distribution within the SNc/VTA region, 
infusion at that site will be stopped. The larger volume gives the operating neurosurgeon greater 
discretion to help match the volume of infusion with the size and shape of the SNc/VTA, which may 
vary from side-to-side and between patients. The number of planned cannula placements will remain at 
two sites per target as specified in the current protocol. If distribution of the vector is sub-optimal, the 
cannula may be repositioned to allow remaining vector to be infused in the SNc. The majority of the 
surgical time is required to 1) place burr holes in the skull at the entry points, 2) position the targeting 
system, 3) align the cannula guide with each target site by intraoperative MRI, and 4) place the MRI- 
compatible infusion cannula. With the single cannula pass delivery, the infusion time should be 30-60 
minutes for the SNc/VTA per hemisphere, reducing the total infusion time for both structures bilaterally 
less than 2 hours. This represents a reduction of up to 50% of the infusion time form the way the vector 
was originally delivered in Groups 1 and 2 (SNc infusion (50 µL) time - 30-60 minutes; VTA infusion 
(30 µL) time - 20-60 minutes for the VTA; total infusion time for both structures bilaterally - up to 4 
hours). Shortening the infusion time will reduce anesthesia time, which is important since AADC 
deficiency subjects present severe autonomic and hemodynamic regulatory dysfunctions and are at risk 
of anesthesia complications for several reasons (i.e., nasal congestion, temperature instability, 
hypotension, and hypoglycemia; Swoboda et al. 1999; Swoboda et al. 2003).. 
7.3.1 Investigational Drug 
The AAV2-hAADC vector consists of an adeno-associated virus, serotype 2 (AAV2) containing human 
AADC complementary DNA (cDNA), human cytomegalovirus (CMV) promoter and 3’UTR sequences. 
AAV2-hAADC is supplied in 0.5 mL aliquots as a suspension at a target concentration of 4.9 x 1012 vector 
genomes per mL. The vector and excipient for dilution will be supplied to the clinical site by the Clinical 

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Vector Core, Children’s Hospital of Philadelphia. 
7.3.2 Handling, Storage and Disposal of Drug 
The vector will be stored in an Investigational Drug Pharmacy at <-60˚C. Just prior to use, the material 
will be thawed by allowing it to come to ambient temperature. 
 
Any manipulation of the vials or the contents in preparation for clinical use will be performed in the 
Investigational Drug Pharmacy with standard safety measures. 
 
Any remaining material and supplies coming into contact with the vector will be disposed of following 
the same procedures as for handling biohazardous human clinical samples. 
7.3.3 Dosing and Dose Escalation 
AAV2-hAADC vector will be delivered bilaterally into the SNc and VTA of the midbrain in a single 
surgical setting via SmartFlow®   cannulae (MRI Interventions Inc.; Product code NGS-NC-02) connected 
to Medfusion infusion pumps (Smiths Medical Inc.). Convection-enhanced delivery (CED) will be used, 
with an increasing infusion rate (1-15 µL/min) to maximize distribution of the vector within the target. 
Both  the  SmartFlow®     cannula  and  Medfusion  pumps  will  be  used  “off-label”  in  this  study  and  are 
considered experimental for this application. 
 
The flowchart for staged dosing is shown in Figure 2. Three subjects meeting the entry criteria will be 
enrolled sequentially in Group 1; a subject must be followed through Month 3 (90 days) post-surgery 
before the next subject in the group may be treated. 
 
A Data and Safety Monitoring Board (DSMB) established by the NIH will review safety data after each 
subject has been treated and will review the accumulated safety and efficacy data. The DSMB will be 
notified of the occurrence of dose limiting toxicities (DLT) (see Section 22.2 for definition) within 5 
business days of the initial report to the Sponsor. If 1 subject experiences a DLT, treatment of additional 
subjects will not proceed until review and approval of the DSMB. If 2 or more subjects experience a 
DLT, both treatment and enrollment will be stopped, pending DSMB review. The occurrence of serious 
safety problems may lead to discontinuation of further treatments, based on pre- determined Stopping 
Rules. 
 
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Group 1 if the study team, DSMB, and study Advisory Committee determine, based on review of 
available data, that dose escalation or reduction is warranted. 
 
The DSMB will review study data once the third subject in Group 1 has reached 3 months post-surgery 
(Fig. 2) and the DSMB report will be shared with FDA. With the approval of the DSMB and FDA three 
subjects also will be enrolled in Group 2. Subjects in Group 2 also will be enrolled sequentially, with a 
minimum of 45 days between dosing of each subject. The DSMB review process for Group 2 will be the 
same as that for Group 1. After the last subject in Group 2 reaches Month 6 post-surgery, the DSMB will 
review safety and clinical outcome data for all subjects in Groups 1 and 2. Clinical outcome endpoints 
include improvement of motor symptoms and gains in motor function. If DSMB review is positive and 
no safety concerns are raised by the experience in Groups 1 and 2, the following groups (Groups 3 and 
4) will be dosed with no time limitations other than those inherent to the scheduling availability for the 
Screening, Baseline and Surgery visits. For Groups 3 and 4 DSMB will review safety data after the 3rd 
subject (in either cohort) reaches 2 months post-surgery. By that time, it is likely the report will include 
safety data for 3 subjects followed for at least 2-3 months, which is the most meaningful period for 
detecting surgery and dose-related complications. After that, the DSMB will review safety data every 6 
months. 
7.3.4 Definition of Dose-limiting Toxicity 
 
DLT is defined as any ≥Grade 3 toxicity, based on the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03, that is determined by the Investigator 
to be at least possibly related to AAV2-hAADC. 
 
7.4 
Procedures for Delivery of AAV2-hAADC 
7.4.1 Preoperative Procedures 
Subjects will undergo standard preoperative evaluations in preparation for surgery. This will include pre- 
operative visits with the study neurosurgeon and anesthesiologist. The medical history will be taken with 
regards to any recent changes in medical status and a review of current prescribed and over-the-counter 
medications. Routine clinical laboratory analyses, including CBC with platelets, blood chemistries, 
PT/PTT and urinalysis, will be reviewed (from screening visit), as well as electrocardiogram. At the 
discretion of the clinical team, additional clinical assessments specific to concurrent medical conditions 

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to ensure subject safety may also be obtained. 
 
Patients with AADC deficiency have an increased risk of hypoglycemia, hypotension, and bradycardia 
during periods of physiological stress due to their peripheral catecholamine deficiency. Treating 
physicians will be made alert to these risks to ensure appropriate preparation and close monitoring during 
all procedures requiring anesthesia, and post-operative care in the intensive care unit. 
7.4.2 CED and Imaging of Distribution 
To overcome the problems associated with current delivery methods, we and others have investigated 
the use of convection, or pressurized infusion, to deliver and distribute molecules and genetic vectors to 
targeted sites within the central nervous system (CNS). Previous methods of delivering AAV into the 
parenchyma by simple injection have not been effective at distributing vector over significant volumes 
of target tissue. In contrast, a technique known as CED (convection-enhanced delivery) uses a specially 
designed reflux-resistant cannula to permit high infusion pressures to be exerted at the cannula tip, 
thereby overcoming the interstitial pressure in the brain and allowing the infusate to permeate large 
volumes of targeted areas in a homogeneous manner. Moreover, by co-infusing a chelated Gadolinium 
contrast reagent (gadoteridol), the distribution of the infusate can be accurately measured by MR 
imaging. The distribution of the gadoteridol closely matches distribution of the infused AAV2 vector 
with no evidence of toxicity (Fiandaca et al. 2009) (Su et al. 2010; Richardson et al. 2011c). Pre-clinical 
and clinical studies have shown that co-delivery of gadoteridol, a widely used contrast agent for MR- 
imaging marketed for intravenous administration and used in this protocol off-label, and real-time MR- 
imaging helps to ensure that the target region is exposed to the investigational agent while minimizing 
exposure of non-targeted CNS tissues (Voges et al. 2003; Lonser et al. 2007b). 
 
The MR images acquired during the CED procedure will be analyzed after surgery to measure the volume 
of gadoteridol contrast enhancement. Calculations will be made of the total volume of gadoteridol 
distribution and percentage of VTA and SN coverage by gadoteridol. Correlations between coverage and 
other outcome measures, such as PET signal may be assessed. 
 
7.4.3 Infusion Procedure 
7.4.3.1 Stereotactic Placement of Infusion Cannula 
Surgery will be performed in a 1.5T or 3T interventional MRI suite. The team at UCSF has used such 

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suites to implant more than 330 deep brain stimulation electrodes since 2004, as well as 7 laser ablations 
(2 Parkinson’s disease, 2 pediatric hypothalamic hematomas and 4 seizure disorders) and 12 CED 
infusions for gene therapy (8 Parkinson’s disease and 4 brain tumors). In addition, many standard 
neurosurgical procedures, including craniotomies and needle biopsies have been performed in the 
interventional MRI suites at UCSF. 
For the procedure, the subject will be placed under general anesthesia and the subject’s head secured to 
an MRI-compatible head-holder attached to the MRI gantry. A combination of volumetric T1, slab T2, 
and slab inversion recovery sequences will be acquired and bilateral VTA and SNc infusion sites and 
cannula trajectories will be identified. Trajectories will be trans-frontal and planned to avoid cortical 
veins and sulci. The surgical sites will be prepared and draped in the usual neurosurgical fashion and 
locally anesthetized. One or two transverse linear incisions will be made in the region of the coronal 
suture. A burr-hole in the skull will be placed, and the dura will be coagulated and opened. Bilateral 
skull-mounted aiming devices (SmartFrame®) will be mounted over each burr-hole. End-lumen cannula 
with a progressive bullet-shaped step design connected to an infusion pump with a syringe containing a 
mixture of AAV2-hAADC and gadoteridol (2 mM) will be placed with its tip in the SNc initially, and 
50 µL of vector will be infused per side with continuous MR imaging to monitor progress of the infusion. 
The cannula will then be repositioned into the ventral tegmental area followed by infusion of 30 µL of 
vector per side. For Groups 3 and 4, the operating neurosurgeon will plan to position the cannula with 
its tip in the space between SNc and VTA initially, and up to 300 µL of vector will be infused per side 
with while MR imaging to monitor progress of the infusion. Depending on the shape of the infusion 
cannula may be inserted deeper along the same trajectory to allow for more complete coverage of VTA 
and SN regions. Infusion may be terminated before reaching full infusion volume once planned coverage 
is achieved. The use of 1 or more cannula insertions to cover the SNc and VTA on each hemisphere (i.e., 
1 cannula insertion for SNc/VTA or 1 cannula insertion for SNc plus 1 cannula insertion for VTA) will 
remain at the discretion of the operating neurosurgeon on the day of surgery based on pre-surgery 
planning that considers individual subject variations in the anatomy of target sites and planned trajectory. 
7.4.3.2 AAV2-hAADC Infusion 
Convection-enhanced delivery will be used, with a stepped infusion rate to maximize distribution of the 
vector within the target. In order to monitor the pattern of infusion, serial intraoperative T1-weighted 
images will be obtained until its completion (images will be acquired every 4 minutes consecutively). If 

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significant backflow along the cannula is detected, the infusion rate may be decreased or the cannula 
may be advanced slightly. If further backflow is still detected or leakage into non-targeted areas is 
observed, and less than half of the intended volume is infused, the infusion will be stopped and 
consideration will be given to moving the cannula to a new infusion site. If backflow or leakage into 
non-targeted areas is seen, and more than half of the intended volume has been infused, the infusion will 
be stopped and no further infusion will be performed in that region. During SNc/VTA, SNc or VTA 
infusion, if infusate is seen distributing along the white matter tracts (descending tracts) in the 
tegmentum, suggesting off target infusion into cranial nerves III - IV, the infusion will be immediately 
halted. All subjects will remain on study regardless of total volume infused. Data will be analyzed with 
and without subjects that receive less than the intended dose of AAV2-hAADC. 
 
Once the full AAV2-hAADC dose has been delivered, the infusion will be terminated. The cannula will 
be removed after terminating the infusion and the incision will be closed with absorbable plates over the 
burr-holes, along with absorbable sutures in the galea and skin. The subject will then undergo final 
imaging to rule out hemorrhage after cannula removal and will then be removed from the scanner. 
7.4.4 Postoperative Procedures 
After leaving the MRI suite, the subject will be extubated and taken to the Pediatric Intensive Care Unit 
(PICU) for observation for the ensuing 48-72 hours. If the subject is stable on postoperative day 3, he/she 
will then be transferred to the children’s floor for the remainder of the hospital stay. 
7.4.5 Discharge Criteria 
The duration of the subject’s hospitalization is expected to be 2-3 days, excluding any complications. 
After hospital discharge, subjects will attend study center visits on an outpatient basis. Discharge criteria 
are as follows: 
 
For transfer from PICU to inpatient floor: 
4. 
Stable cardiorespiratory status off mechanical ventilation and pressor support for at 
least 24 hours 
5. 
Awake and alert 
6. 
Stable neurological examination for 24 hours 
7. 
No evidence of hemorrhage on brain MRI 48 hours after surgery 
8. 
If post-surgery brain MRI shows hemorrhage, then PICU discharge will be subject to 

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neurosurgical clearance following further clinical monitoring and follow-up brain 
imaging. 
From hospital: 
1. 
Baseline level of alertness 
2. 
No requirement for respiratory support or oxygen 
3. 
Able to tolerate usual diet or enteral feeds 
4. 
Stable neurological examination for 48 hours 
From clinical site: 
1. 
Able to comfortably tolerate all routine daily activities including mobility, sleep, and 
feeding 
2. 
Stable medication regimen for 3 days. 
 
7.4.6 Management of Post-therapy Dyskinesia 
 
Gene transfer is expected to result in an increase in brain dopamine production within approximately 1 
month after surgery. One anticipated effect of the increase in dopamine is the occurrence of involuntary 
jerky or writhing movements (dyskinesia). Based on the prior experience with putaminal transfer of 
hAADC in a total of 8 patients with AADC deficiency (Hwu, 2012), and the experience of others in 
treating congenital dopamine deficiency with levodopa (Pons, 2013), dyskinesia is expected to subside 
over weeks to months, as compensatory changes in postsynaptic dopamine receptors occur in response 
to the increase in nigrostriatal dopamine. 
Subjects will be monitored frequently for dyskinesia in the 3 months after gene transfer by the study 
team via teleconference, and the clinical course will be followed closely and documented via serial video 
examinations at specific visits. The severity of dyskinesia is to be assessed by the Investigator using the 
guidelines in Table 3. 
Suggested guidelines for medical management of dyskinesia can be found in Appendix 9. 
 
Table 3: Grading of Post-therapy Dyskinesia 
 
Grade 1 
Mild, low amplitude movements which cause no functional impairment. Child is able 
to sit (supported or unsupported) comfortably and has regular periods of uninterrupted 
sleep. 
 
Grade 2 
Mild-moderate movements, associated with minor disruption to routine care or 
interference with sitting. Child may have some difficulty settling to sleep. 

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Grade 3 
Moderate-severe movements causing significant discomfort and/or self-injury. Unable 
to get to sleep. No evidence of metabolic compromise (i.e. normal hydration status, 
electrolytes, renal function, with CK <1,000 IU/L) 
 
Grade 4 
Severe movements causing significant discomfort and/or self-injury. Unable to get to 
sleep. Evidence of metabolic decompensation (e.g. elevated BUN or creatinine, CK 
>1,000 IU/L 
Modified from Dystonia Severity Action Plan (Lumsden, 2013, Dev Med Child Neurol). 
 
8 
SAFETY AND RESEARCH ASSESSMENTS 
 
Safety assessments include: 
 
• co-infusion of gadoteridol with AAV2-hAADC to confirm dosing to appropriate region 
• intraoperative and post-operative MRI 
• grading of adverse events 
• physical examinations 
• routine clinical laboratory analysis (hematology, clinical chemistries, immunologic assessments) 
 
8.1 
Clinical Assessments 
8.1.1 Adverse Event (AE) Log 
A systematic assessment of adverse events and side effects will be performed at all study visits based on 
standardized discussions with the subject's caregiver using open-ended questions. Information will be 
systematically recorded on an Adverse Events (AE) Log which includes type of AE, dates of onset and 
resolution, severity, perceived relationship to experimental therapy. The severity of each AE will be 
rated based on the NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE; Appendix 2). 
8.1.2 Medication Log 
The use and dosages of medications will be systematically recorded. A substantial decline in medication 
requirement may provide evidence of a beneficial effect of our experimental therapy. 
8.1.3 Behavior Diary 
 
A standardized Behavior Diary (Appendix 7) will be used to capture the frequency and duration of 
clinical symptoms caused by brain dopamine dysregulation. 
• One category of symptoms is attributable to dopamine deficiency, and includes oculogyric 

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crises and dystonic episodes. 
• The second category is treatment-related involuntary movements, or dyskinesia, which is 
attributed to dopamine receptor hypersensitivity induced by chronic dopamine deficiency. 
Patients may experience dyskinesia pre-treatment, due to their oral medications, and/or post- 
treatment, due to increased endogenous production of brain dopamine as a result of the gene 
transfer. 
• The third category of symptoms is pre- or post-treatment psychiatric and behavioral symptoms, 
which may manifest as changes in behavior and/or sleep. 
 
Subject's caregivers will be trained in the completion of a behavior diary by study center personnel during 
Screening. The behavior diary then is to be completed twice during the period between the Screening 
and Baseline visits, each over a consecutive 7-day period at least 1 month apart. The diary will be 
reviewed by study center personnel for legibility and completeness. If there are any difficulties in 
interpreting the diary, the caregiver will be retrained. If the caregiver reports difficulty in recalling how 
to record the subject diary for subsequent visits, he or she will be retrained by study center personnel. In 
addition to the intermittent 7-day Behavior Diary, caregivers will be asked to keep a separate log of 
oculogyric crises in real time during study participation. 
8.1.4 Medical and Neurologic Examinations 
A general medical and a full neurologic examination will be conducted and any abnormality will be 
recorded. 
Some neurological examinations will be recorded on video, with the aim of documenting changes in 
motor function from baseline over time, and documenting the evolution of involuntary movements that 
may emerge after surgery. Video examinations may also be viewed and scored by independent, blinded 
raters in the process of data analysis. All subjects will have a brief examination recorded on video at 
Baseline, 1 month, weekly between 1 and 2 months, 3 months, 6 months, 12 months, 24 months, 36 
months, 48 months and 60 months (See Video Protocol, Appendix 10). If motor symptoms emerge at 
other points in time, additional recordings may be made at the discretion of one of the study neurologists. 
Video recordings will be transferred immediately from the camera to an encrypted desktop or laptop 
computer (endpoint device), and deleted from the camera storage card. The files will be stored 
indefinitely. 

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Steps will be taken to protect subject identity and privacy as much as possible. Subjects will not be 
identified by name on the video. Each video filename will contain only the subject's numerical 
identification code and date of recording. Recording of the face will be limited to only what is necessary 
to adequately demonstrate the relevant clinical features. If the study investigators show brief video 
excerpts at any future scientific presentations, the identity of subjects will be protected by masking the 
face unless it is not possible to do so in the event that a facial symptom is being illustrated. 
 
8.2 
CSF, Blood and Urine Neurotransmitter Analytes 
8.2.1 CSF Neurotransmitter Analytes 
CSF will be collected by lumbar puncture, to be performed with sedation if necessary. (See Appendix 3 
for CSF collection protocol) 
 
Metabolites to be assayed: 
• Homovanillic acid (HVA) 
• 5-Hydroxyindoleacetic acid (5-HIAA) 
• 3-O-methyldopa (3-OMD) 
• 5-methyltetrahydrofolate (5-MTHF) 
8.2.2 Plasma AADC and 3-O-Methyldopa Activity 
Plasma AADC enzyme activity and 3-OMD levels will be determined by quantitative methods (Hyland 
and Clayton 1992). It will be performed by Medical Neurogenetics, Atlanta GA (Appendix 3). 
8.2.3 Urine vanillactate 
Vanillactate is a metabolite of 3-OMD, and may be assayed in urine, together with other urine organic 
acids, using tandem mass spectrometry. A quantitative assay is under development (Dr. Simon Heales, 
Great Ormond Street Hospital, London, UK). Urine samples will be collected so that we may correlate 
urine vanillactate with CSF 3-OMD levels to explore its future potential as a biomarker that may be 
performed non-invasively. 
 
Sample requirements: 5 mL random fresh urine, frozen immediately at -20 C for storage and transport. 
 
8.3 
Clinical Measures 
The following measures will assess motor and cognitive function, adaptive behavior, and patient/family 

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quality of life. They are collectively referred to in the Schedule of Events table as "Motor /QoL 
Measures." These measures will be obtained at Baseline, 3 months, 6 months, 12 months, 18 months, 24 
months, 36 months, 48 months and 60 months. 
8.3.1 GMFM-88 
The GMFM is a standardized instrument to evaluate changes in gross motor function over time in 
children (Russell et al. 2002). It has been validated in patients with cerebral palsy. It is designed to assess 
how much of an activity a child can accomplish, rather than the quality of the motor performance, across 
five dimensions: lying/rolling, sitting, crawling/kneeling, standing, and walking/running/jumping. Each 
dimension contributes 20 percentage points towards a total possible score of 100. We expect that, at 
baseline, most subjects will have very limited voluntary movement and will lack the ability to sit without 
support (baseline score <30). If gene transfer successfully restores dopamine production, we anticipate 
that subjects will experience gradual improvement in trunk control, mobility, and voluntary reaching and 
grasping movements. We estimate that this could correspond with an approximate 10 point increase in 
GMFM score at 12 months. (Appendix 4). 
8.3.2 Pediatric Evaluation of Disability Inventory (PEDI) 
The PEDI, originally published in 1992 (Haley et al. 1992), was revised as a computer adaptive test, the 
PEDI-CAT, in 2012 (Dumas and Fragala-Pinkham 2012; Dumas et al. 2012). The PEDI-CAT is designed 
for use with children and youth (birth through 20 years of age) with a variety of physical and/or 
behavioral conditions. It measures abilities in 3 functional domains: Daily Activities, Mobility, 
Social/Cognitive. (A fourth domain, Responsibility, assesses abilities in more complex tasks that enable 
independent living, and will not be applicable to our study population). The PEDI-CAT takes 10-15 
minutes for parents to complete. The software utilizes Item Response Theory statistical models to 
estimate a child’s abilities from a minimal number of the most relevant items or from a set number of 
items within each domain. All respondents begin with the same item in each domain in the middle of the 
range of difficulty or responsibility and the response to that item then dictates which item will appear 
next (a harder or easier item), thus tailoring the items to the child and avoiding irrelevant items. For each 
item, the child's ability is rated on a 4-point difficulty scale with responses ranging from ‘Unable’ to 
‘Easy’. The CAT generates scaled scores, which can be used to follow changes in a child’s functional 
skills over time (Appendix 5). 

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8.3.3 Vineland Adaptive Behavior Scales-2nd edition 
The Vineland-II is designed to measure the adaptive behavior of individuals across the domains of 
communication, daily living skills, and socialization. The questions are administered in the form of an 
interview with the child’s caregivers and will be administered at Baseline, and 12 and 24 months. 
8.3.4 Pediatric Quality of Life Inventory (PedsQL™) 
The PedsQL is a modular instrument for measuring health-related quality of life in children and 
adolescents ages 2 to 18 years. The PedsQL 4.0 Generic Core Scales questionnaire (Varni et al. 2001; 
(Appendix 6)) contains 23 items and takes approximately 5-10 minutes for parents to complete. Children 
aged 5 and over may complete a corresponding self-report questionnaire if able. (We anticipate that most 
if not all of the subjects in this study will not be able to complete it themselves). The questionnaire yields 
information on the physical, emotional, social and school functioning of the child during the previous 4 
weeks. Each item on the scale is reverse-scored on a 0-4 scale, and raw scores are transformed to a 0- 
100 scale and averaged, so that higher scores indicate better quality of life. 
8.3.5 Patient/Caregiver Global Impression of Change (PGI-C) 
Caregivers will be asked to provide a global impression of change in the subject's overall functional level 
and quality of life on a 7-point scale ranging from 1 (much worse) to 7 (much better). The PGI-C will be 
completed 3, 6, 12, 18, and 24months after gene transfer. 
8.3.6 Caregiver Priorities and child health Index of Life with Disabilities Questionnaire (CP Child) 
Caregivers will be asked to assess the health status, comfort, wellbeing and ease of caregiving of children 
with severe cerebral palsy. We are using cerebral palsy as the closest disability comparison to AADC 
deficiency. 
8.3.7 Cognitive and Developmental Assessments 
We will explore the potential utility of established developmental and cognitive assessments in our study 
population. Their use may be limited as a result of our subject’s severe physical disability. 
Developmental  assessments,  including the Peabody  Developmental  Motor Scales 2nd    edition (PDMS- 
will be attempted. The study neuropsychologist will try to administer cognitive assessments in which 
responses may be given by pointing rather than speaking (e.g., Peabody Picture Vocabulary test, Raven’s 
Progressive Matrices). 
 

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8.4 
Neuroimaging 
8.4.1 MR-imaging 
MR-scans will be performed pre-operatively as part of the screening process, during the infusion 
procedure, and then at 48 hours and 24 months postoperatively. 
 
Scans may be obtained at other time-points if deemed necessary by the investigators. Sequences will be 
obtained on a 3T field strength MRI and will include full head 3D high resolution T1 with contrast, 3D 
T2, Diffusion Tensor Imaging (DTI), and susceptibility weighted imaging (SWAN). The projected 
duration of the imaging study will be less than 1 hour. The 48 hour MR scan will use a ‘rapid’ protocol 
and will consist of a 3D T2 FSE sequence, and axial diffusion; the anticipated duration of this study is 
15 minutes. Sedation is typically not required for the ‘rapid’ protocol. Any abnormalities, seen as a 
change from the screening MR imaging and not anticipated from the surgical procedure, will be reviewed 
by the study neurosurgeon and neuroradiologist and reported as an AE. 
8.4.2 [18F]-FDOPA Positron Emission Tomography (PET) 
[18F]-FDOPA  is  a  PET  radiopharmaceutical  that has  been  used  for  approximately  30  years  to  image 
dopamine synthesis capacity. It has been used for clinical research purposes in thousands of patients to 
study neuropsychiatric disorders, patients with neuroendocrine disorders, as well as in healthy controls. 
It has been widely used in both patients and normal control subjects. Details of the production have been 
provided in IND #15660. 
Brain [18F]-FDOPA PET scans may be performed at screening, 3 months and 24 months. In cases when 
it is not in the subject’s best interest to undergo procedure under prolonged anesthesia and/or subject 
presents travel limitations, the PET scan might be not performed. The dose of 0.043mCi/kg for F-DOPA 
is a weight-based dose calculation that will allow a safe dose yet produce a more detailed scan and 
optimal visualization of the brain (Barthlen et al. 2008; Liu et al. 2016). Weight based dosing will not 
exceed 3 mCi per injection (RUA approval: RU133031-01A). We anticipate that subjects will require 
sedation to remain still during the scan. Sedation will be administered by a pediatric anesthesiologist. 
PET scans will be analyzed for quantification of AADC activity and differences in the distribution of 
AADC activity between baseline and post-surgery scans. 
 
Fluorinated radiopharmaceutical emits a little amount of radiation. They have been used in the research 
and clinical arenas for more than 30 years with no measurable adverse effects. 

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8.4.3 DaTscan™ Ioflupane I-123 SPECT 
 
DaTscan imaging may be performed as part of subject screening if, after reviewing the subject’s medical 
history and screening materials, the study clinical team deems necessary will be performed to assess the 
integrity of the nigrostriatal pathway. Ioflupane I-123 selectively binds to presynaptic dopamine 
transporters and provides a method for imaging nigrostriatal terminals in the striatum. DaTscan™ is an 
FDA-approved radiopharmaceutical used in conjunction with single photon emission computed 
tomography (SPECT) scan for use in adults. DaTscan will be performed at the screening visit to 
document nigrostriatal pathway integrity. 
 
Iodine-123  is  a  cyclotron-produced  radionuclide  that  decays  to  123Te  by  electron  capture  and  has  a 
physical half-life of 13.2 hours. The recommended dose is 111 to 185 MBq (3 to 5 mCi) administered 
intravenously in adults. The estimated radiation absorbed doses to an average adult from intravenous 
injection of DaTscan are shown in Table 1. The values are calculated assuming urinary bladder emptying 
at 4.8-hour intervals and appropriate thyroid blocking (iodine-123 is a known Auger electron emitter). 
 
Table 4: Estimated Radiation Absorbed Doses from DaTscan 
ORGAN / TISSUE 
ABSORBED DOSE PER UNIT ADMINISTERED ACTIVITY 
(µGy / MBq) 
*The absorbed dose to the colon wall is the mass-weighted sum of the absorbed doses to the upper and lower large intestine 
walls, D Colon = 0.57 DULI + 0.43 DLLI [Publication 80 of the ICRP (International Commission on Radiological 
Protection); Annals of the ICRP 28 (3). Oxford: Pergamon Press; 1998] 
Adrenals 
12.9 
Brain 
17.8 
Striata 
230.0 
Breasts 
7.8 
Esophagus 
10.0 
Gallbladder Wall 
26.4 
GI Tract 
Stomach Wall 
11.2 
Small Intestine Wall 
21.2 
  
Colon Wall * 
39.8 
  
Upper Large Intestine Wall 
38.1 
  
Lower Large Intestine Wall 
42.0 
  
Heart Wall 
12.9 
 
Kidneys 
10.9 
 
Liver 
27.9 
 
Lungs 
41.2 
 
Muscle 
9.4 
 
Osteogenic Cells 
28.2 
 

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ORGAN / TISSUE 
ABSORBED DOSE PER UNIT ADMINISTERED ACTIVITY 
(µGy / MBq) 
Ovaries 
16.8 
 
Pancreas 
13.0 
 
Red Marrow 
9.2 
 
Skin 
6.0 
 
Spleen 
10.4 
 
Testes 
8.5 
 
Thymus 
10.0 
 
Thyroid 
9.0 
 
Urinary Bladder Wall 
53.1 
 
Uterus 
16.1 
 
Total Body 
11.3 
 
EFFECTIVE DOSE PER UNIT 
ADMINISTERED ACTIVITY 
(µSv / MBq) 
21.3 
 
 
The Effective Dose resulting from a DaTscan administration with an administered activity of 185 MBq 
(5 mCi) is 3.94 mSv in an adult. 
The DaTscan injection may contain up to 6% of free iodide (iodine 123). To decrease thyroid 
accumulation of iodine-123, a dose up to 100 mg of Potassium Iodide Oral Solution or Lugol's Solution 
will be administered. 
8.5 
Hematology, Clinical Chemistry and Immunological Assessments 
Routine hematology and clinical chemistry assessments will be performed on blood samples collected 
at Screening, 1 week after surgery, and as clinically indicated in the post-operative period. Blood 
coagulation parameters will be assessed 1-10 days prior to surgery. 
 
Blood samples will be collected at Screening, and Months 1, 3, and 6 to measure levels of neutralizing 
anti-AAV2 antibodies (nAb): Samples will be stored at <-60°C and analyzed in groups after completion 
of each dose group. Samples will be analyzed in conjunction with any observed clinical events. These 
assays are being obtained for research purposes, and safety information cannot be obtained from them 
alone. 
 
Hematology: Hemoglobin (Hgb), Hematocrit (Hct), Red Blood Cells (RBC), Mean Corpuscular Volume 
(MCV), Mean Cell Hemoglobin (MCH), Mean Cell Hemoglobin Concentration (MCHC), White 
Blood Cells (WBC), Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Platelets 
 

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Clinical Chemistry: Blood Urea Nitrogen (BUN), Creatinine, Sodium, Potassium, Chloride, 
Bicarbonate, Magnesium, Phosphorus, Calcium, Glucose, Total Protein, Albumin, Total Bilirubin, 
Alkaline Phosphatase (ALP), Serum Glutamic Aminotransferase/Aspartate Transaminase 
(SGOT/AST), Serum Pyruvate Aminotransferase/ Alanine Aminotransferase (SGPT/ALT), Gamma-
glutamyl transpeptidase (GGT) 
 
Coagulation studies: PT, aPTT, INR, Thrombin Time, and Fibrinogen 
 
Immunological Assessment: Determination of anti-AAV2 Capsid Neutralizing Serum Antibodies. 
Samples will be collected at Screening and Month 3 and banked until further analysis. 
 
9 
SCHEDULE OF STUDY ASSESSMENTS 
 
Patients with AADC deficiency are a fragile population, thus, when possible, the option will be open for 
the subject to have a scheduled visit at the clinical site or, if it is not in the subject’s best interest to travel, 
the study team will visit her/him at their home place. 
 
The Schedule of Assessments is detailed in Appendix 1; assessments by Visit are listed below. 
 
9.1 
Pre-Screen 
• Medical History 
• Prior Medications 
• Current Medications (screen for medications that need to be discontinued prior to LP; 
see section 10, “Medications for AADC Deficiency,” below) 
• Review previous results of CSF neurotransmitter analysis, molecular genetic testing, 
and plasma AADC enzyme assay 
9.2 
Screening (Day -56 to Day -11) 
• Informed Consent 
• Medical History 
• Physical Exam/Vitals 
• Neurological Exam 
• Anesthesia Consult 

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• Social Worker Visit 
• 12 lead ECG  
• Brain MRI 
• FDOPA PET Scan (AADC activity), if possible 
• Baseline Neurotransmitter Analytes (CSF, Blood, Urine) - #1 of 2 
• Prior Medications 
• Current Medications 
• Clinical Chemistry 
• Hematology 
• Coagulation studies 
• Immunology (AAV-nAb) 
• Blood Sample (PCR) 
• If needed, DaTscan™ Ioflupane I-123 SPECT 
9.3 
Baseline (Day -10 to D -1) 
• Physical Exam/Vitals 
• Neurological Exam - videotaped 
• Type and Screen (may be done on day of surgery – day 0, at discretion of surgeon) 
• Motor/Quality of Life Measures 
• Cognitive Assessment 
• Behavior Diary 
• Oculogyric Crisis Log 
• Adverse events 
• Current medications 
9.4 
Surgical Delivery of AAV2-hAADC – Pre Surgery & Surgery (Day 0) 
• Physical Exam/Vitals 
• Neurosurgical Exam 
• Baseline Neurotransmitter Analytes (CSF, Blood, Urine) - #2 of 2 
• MRI-Guided surgery 
• Adverse events 
• Current Medications 

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9.5 
Hospital Stay (Day 2) 
• Physical Exam/Vitals 
• Brain MRI (rapid scan protocol) at ~ 48 hours 
• Neurosurgical Exam 
• Current Medications 
• Adverse Events 
 
9.6 
Treatment Follow-up Phase 
9.6.1 Visit 1 (day 10 +/- 4 days; at clinical site or clinic close to home) 
• Physical Exam/Vitals 
• Neurological Exam 
• Neurosurgical Exam (includes suture removal) 
• Current Medications 
• Adverse Events 
9.6.2 Visit 2-5 (day 28, 35, 42, 49 +/- 3 days - videoconference) 
• Behavior Diary 
• Oculogyric Crisis Log 
• Current Medications 
• Adverse Events 
Between Visit 2 and Visit 5 subjects will be contacted by videoconference at least once per 
week (Days 28, 35, 42 and 49). This is the period when post-surgery dyskinesia may emerge 
and require active management. 
9.6.3 Visit 6 (day 56 +/- 3 days - videoconference) 
• Current Medications 
• Adverse Events 
9.6.4 Visit 7 (Month 3 +/- 14 days) 
• Physical Exam/Vitals 
• Neurological Exam - videotaped 
• Social Worker Visit as indicated/requested 

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• Clinical Chemistry 
• Hematology 
• Immunology (AAV nAb) 
• Neurotransmitter metabolites (CSF, Blood, Urine) 
• Motor/QoL Measures 
• PGI-C 
• Behavior Diary 
• Oculogyric Crisis Log 
• FDOPA PET Scan (AADC), if possible 
• Blood sample (PCR) 
• Current Medications 
• Adverse Events 
9.6.5 Visit 8 (Month 6 +/- 14 days) 
• Physical Exam/Vitals 
• Neurological Exam - videotaped 
• Social Worker Visit as indicated/requested 
• Neurotransmitter metabolites (CSF, Blood, Urine) 
• Motor/QoL Measures 
• Behavior Diary 
• Oculogyric Crisis Log 
• Current Medications 
• Adverse Events 
9.6.6 Visit 9 (Month 12+/- 14 days) 
• Physical Exam/Vitals 
• Neurological Exam - videotaped 
• Neurotransmitter metabolites (CSF, Blood, Urine) 
• Motor/QoL Measures 
• PGI-C 
• Cognitive Assessment 

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• Behavior Diary 
• Oculogyric Crisis Log 
• Current Medications 
• Adverse Events 
9.6.7 Visit 10 (Month 18+/- 14 days) 
• Physical Exam/Vitals 
• Neurological Exam - videotaped 
• Motor/QoL Measures 
• PGI-C 
• Behavior Diary 
• Oculogyric Crisis Log 
• Current Medications 
• Adverse Events 
9.6.8 Visit 11 (Month 24+/- 14 days) 
• Physical Exam/Vitals 
• Neurological Exam - videotaped 
• Brain MRI 
• Neurotransmitter metabolites (CSF, Blood, Urine) 
• Motor/QoL Measures 
• PGI-C 
• Cognitive Assessment 
• Behavior Diary 
• Oculogyric Crisis Log 
• FDOPA PET Scan (AADC), if possible 
• Current Medications 
• Adverse Events 
9.6.9 Visit 12 (Month 36 +/- 14 days) 
• Physical Exam/Vitals 
• Neurological Exam - videotaped 

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• Motor/QoL Measures (only GMFM) 
• Oculogyric Crisis Log  
• Current Medications 
• Adverse Events 
9.6.10 Visit 13 (Month 48 +/- 14 days) 
• Physical Exam/Vitals 
• Neurological Exam - videotaped 
• Motor/QoL Measures (only GMFM) 
• Oculogyric Crisis Log  
• Current Medications 
• Adverse Events 
9.6.11 Visit 14 (Month 60 +/- 14 days) 
• Physical Exam/Vitals 
• Neurological Exam - videotaped 
• Motor/QoL Measures (only GMFM) 
• Oculogyric Crisis Log  
• Current Medications 
• Adverse Events 
 
10 MEDICATIONS FOR AADC DEFICIENCY 
 
We anticipate that most subjects will be taking multiple medications for management of AADC 
deficiency at the time of entry into the trial. Medications commonly used to treat AADC deficiency, such 
as dopamine agonists, pyridoxine, pyridoxal phosphate, selegiline (or other MAO inhibitor), and 
trihexyphenidyl, are permitted. We require that no new medication have been started in the 6 months 
prior to Baseline, and that doses have been stable for 3 months prior to Baseline. 
 
If a DaTscan is deemed necessary, it needs to be taken into account that some medications interfere with 
DAT SPECT (Appendix 8). The medications listed above do not, but some patients may be taking other 
medications. For example, selective serotonin reuptake inhibitors (SSRI's) interfere with DAT SPECT 
and would need to be discontinued before the scan (recommended stopping time prior to scan is ≤8 days 

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for all SSRI's except fluoxetine, which needs to be stopped 45 days prior). 
Levodopa would cause elevation of CSF 3-OMD beyond the level due to the primary disease and 
confound post-operative measurements that will be relied upon to assess the effect of gene transfer. 
Levodopa must be discontinued at least 7 days prior to lumbar puncture. 
 
At the time of pre-screening, all of the subject's medications will be reviewed. In the event that any 
subject needs to undergo a DaTscan and is taking levodopa or a medication that would interfere with 
DAT SPECT, a recommendation will be made to taper the medication off 3 months prior to the Screening 
visit. 
 
Any patient treated with a rotigotine patch should have the patch removed prior to MRI scan (the patch 
contains aluminium). 
 
11 POST-MORTEM BRAIN EXAMINATION 
 
Each subject's parent(s)/guardian(s) will be informed that, in the event of death, even after completing 
the formal protocol, careful neuropathological examination of the brain is desirable and encouraged. 
Information will be provided to families regarding the process of brain donation. Gross and microscopic 
examinations will seek the location of needle tracks and the localization of the infusion sites. Post- 
mortem analysis may include assessment of frozen or fixed brain sections. Immunohistochemistry for 
AADC will be performed to assess gene transfer. 
 
12 SUBJECT WITHDRAWAL / DISCONTINUATION OF STUDY 
 
12.1 Voluntary Participation 
Participation in this study is voluntary. All subjects have the right to withdraw at any point during the 
study with no penalty or loss of benefits to which the subject is otherwise entitled. Every attempt will be 
made to provide safety follow-up for the subject. Subjects who withdraw for reasons other than 
safety/tolerability will be replaced. 
The Principal Investigator may withdraw a subject from the protocol if the subject is unwilling or unable 
to comply with the requirements of the protocol. 
12.2 Discontinuation of the Study 
In the course of the study, if the Investigator, the DSMB, or the Food and Drug Administration discover 

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conditions including, but not limited to, the discovery of an unexpected, serious, or unacceptable risk to 
subjects, the study will be discontinued. 
 
13 RISKS/DISCOMFORTS 
 
13.1 Neurosurgical Complications 
Known complications of real time image guided brain infusion fall into four groups: 1) risks associated 
with intra-cerebral infusion, 2) risks associated with infusion of MRI contrast agent, 3) immediate 
complications that occur during the actual procedure, and 4) delayed complications that occur in the 
postoperative period. 
 
13.1.1 Risks of Intra-cerebral Infusion 
Direct delivery within the interstitial space of the brain has been safely performed in numerous clinical 
studies. Previous gene transfer studies for Parkinson’s disease include direct infusion into the putamen, 
substantia nigra and subthalamic nucleus. Approximately 250 subjects have been treated in these 
previous studies. 
 
No SAEs related to the AAV2-hAADC vector were reported in the two clinical studies, at UCSF and 
Jichi Medical University, completed to date (Christine et al. 2009; Muramatsu et al. 2010). In both open- 
label studies the same AAV2-hAADC vector was directly delivered to the putamen. However, out of the 
16 subjects treated, four subjects had cerebral hemorrhages (two asymptomatic and two symptomatic 
with almost complete recovery). In the UCSF trial (10 subjects) two intracranial hemorrhages (one 
subject in each dose cohort) and a cerebral venous infarction (subject in low dose cohort) were early 
events that occurred on the day of surgery (temporally related; Christine et al. 2009). Of the 6 subjects 
enrolled in the Jichi Medical University study, one subject experienced a venous hemorrhage in the right 
frontal lobe beneath and anterior to the burr hole, which resulted in symptoms related to hemorrhage and 
surrounding edema. All hemorrhages occurred along the trajectory of the catheters but far from the 
infusion site and were unrelated to the infusion of AAV2-hAADC. The subjects in these original two 
studies were treated a number of years ago, and with improved targeting techniques being used in current 
trials, we believe the likelihood of significant hemorrhage is reduced. An additional 18 patients have 
been treated in ongoing trials without the occurrence of any cerebral hemorrhage (personal 
communication from PI’s). 

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A critical aspect of the infusion procedure for this study is the use of convection-enhanced delivery 
(CED, allowing for small and large molecules to be distributed within deep brain structures in a highly 
reliable, homogenous, and targeted manner (Laske et al. 1997a; Lonser et al. 2002) (Gill et al. 2003). 
This technique has been used clinically to deliver immunotoxins over large volumes of brain parenchyma 
(several magnitudes larger than what would be used in this study) in patients with brain tumors. In a 
Phase 1 study conducted at the NIH by the Surgical Neurology Branch, there were reported 4 instances 
(in 2 of 28 patients) of cerebral hemorrhage occurring at 79 days (median) after the start of drug infusion, 
and 1 instance of hydrocephalus occurring 125 days after infusion. These complications were attributed 
to the tumor biopsy obtained before beginning the infusion or to the immunotoxin therapy itself, rather 
than catheter placement or this method of delivery. Another Phase 1 study of CED of immunotoxins in 
15 adult tumor patients reported no complications from catheter placement or CED (Laske et al. 1997b). 
A Phase 2 study of CED of the Tf-CRM107 immunotoxin in patients with glioblastoma was recently 
completed at the NIH and cooperating centers, and again the infusion was not linked to any 
complications. More recently, there have been 11 AADC deficiency patients that received a CED 
infusion of AAV2-AADC into the midbrain under an EC-approved CUP at the Mazovian Bródnowski 
Hospital in Warsaw, Poland. No SAEs related to the investigational product or the surgical procedure 
were reported. 
 
13.1.2 Risks of Gadoteridol Co-Infusion 
Co-infusion of a gadolinium-based imaging agent allows MRI detection of vector distribution within the 
brain. No histopathologic evidence of gadolinium-related changes or toxicity have been observed in non-
human primate studies when infused in the brain via CED. Gadoteridol (ProHance) has proved to be an 
excellent imaging marker for gene expression after intra-cerebral CED of AAV2 vectors. 
 
Several clinical studies have been performed that included the direct infusion of gadoteridol in the human 
CNS with no evidence of toxicity related to gadolinium. A Phase 1/2 clinical trial for glioblastoma 
multiforme involved cerebral infusion of gadolinium-DTPA (1 mM) before delivery of a liposomal 
vector bearing the HSV-1-tk gene (Voges et al. 2003). The NIH has treated an 8-month-old male with 
neuronopathic (type 2) Gaucher’s disease with glucocerebrosidase administered via CED to the 
brainstem co-infused with gadolinium-DTPA to monitor infusate distribution and a 3-year-old female 
with diffuse brainstem glioma with interleukin 13-Pseudomonas exotoxin administered via CED to the 

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brainstem co-infused with gadolinium-DTPA to monitor infusate distribution (Lonser et al. 2007a; 
Lonser et al. 2007b). Similar CED parameters (as outlined in this protocol) were used in these patients 
and they tolerated infusions without clinical or radiographic evidence of toxicity. More recently, a study 
was conducted at UCSF involving CED of gadoteridol (ProHance) and a retroviral replicating vector 
encoding cytosine deaminase into glioblastoma multiforme tumors (ClinicalTrials.gov identifier: 
NCT01156584). 
 
Gadolinium-based contrast agents are marketed for intravenous administration to visualize lesions in the 
central nervous system with MRI. In a typical gadolinium-contrast enhanced MRI scan with ProHance, 
a 70-kg man would receive approximately 3,900 mg of gadolinium intravenously. In the study proposed 
here, subjects will receive gadoteridol at a maximum concentration of 2.8 mg/mL in a volume of 0.9 mL 
delivered intra-cerebrally, i.e. 2.5 mg gadoteridol, more then 1,500-fold less than the amount delivered 
during a typical intravenous MRI study. It should be noted that all subjects will also have intravenous 
gadoteridol administered for a routine contrast-enhanced MRI on the day of surgery to assist with 
surgical planning. Intra-cerebrally administered gadoteridol is used “off label” in this study and is 
considered experimental. 
 
The most common side effect associated with systemic administration of gadolinium-based contrast 
agents is headache with an incidence of 4.8%. The majority of headaches are transient and of mild-to- 
moderate severity. Nausea is the second most common side effect at 2.7%. Injection site 
coldness/localized coldness is the third most common side effect at 2.3%. Dizziness occurs in 1% of 
patients. People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
nephrogenic systemic fibrosis, which has resulted in a very small number of deaths. 
 
13.1.3 Immediate Surgical Complications 
Misalignment or slippage of the neurosurgical guidance system during surgery would result in loss of 
accurate target localization and any surgical infusion not completed by that point will be aborted if the 
error cannot be corrected. Air embolism, or entry of air into the venous circulation through the vascular 
spaces in the bone of the skull or by cerebral veins, can cause oxygen desaturation and hypotension if 
significant. The risk of this is much lower in this procedure than in many other stereotactic procedures 
as the subject is supine in the MRI. Air embolisms have not been observed in any of our MRI guided 
DBS implantations. Should an air embolism occur, the surgical field will be flooded with irrigation 

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solution immediately. If the surgeon and anesthesiologist deem that the embolism is causing persistent 
and/or significant oxygen desaturation or hypotension, the surgical procedure will be stopped. Subjects 
will undergo frequent MR imaging during surgery, which will allow the detection of any of intracranial 
hemorrhage that may occur. The procedure will be stopped if any evidence of intracranial hemorrhage 
is detected on imaging. 
 
13.1.4 Delayed Surgical Complications 
Cerebral hemorrhage or infarction has been observed with comparable brain surgery procedures (e.g., 1- 
3% of patients undergoing deep brain stimulation experience cerebral hemorrhage resulting in stroke). 
Hemorrhage could result from an arterial vessel puncture as a result of introducing the device into the 
brain, which would result in bleeding immediately or within 24 hours. Arterial bleeding events are more 
likely to be symptomatic with parenchymal involvement manifesting as acute neurological symptoms. 
A hemorrhage resulting from a venous vessel puncture could be slower to appear and more likely to be 
asymptomatic as the blood takes longer to accumulate. Delayed, asymptomatic hemorrhages or venous 
infarctions can be detected on postoperative MR or CT imaging; if found, they will be reported as an 
SAE but will not alter the evaluation schedule. Symptomatic hemorrhages or infarcts will be managed 
with supportive care and intervention appropriate to the degree and location of the lesion. 
 
Infections can involve the surgical wounds superficially, or may be deep infections. Any evidence of 
infection will be reported immediately and will result in immediate evaluation by the neurosurgeon. 
Superficial wound infections may be treated aggressively with antibiotics. Deep infection may be 
explored surgically. No more than 1 subject will be expected to have a central nervous system infection 
based on a 9.0% rate (Weaver et al. 2009). 
 
13.2 Immune Response, Vector and Gene Therapy Risks 
Preclinical studies show that peripherally circulating neutralizing antibodies to AAV can affect the 
efficiency of transduction in gene transfer experiments (Peden et al. 2004; Sanftner et al. 2004; Peden et 
al. 2009). No adverse effects attributed to the presence of neutralizing AAV antibodies have been 
clinically observed, even in human subjects with high antibody titers prior to AAV delivery. Systemic 
levels of AAV2 antibodies will be assessed in this study and may be analyzed in conjunction with adverse 
events or other outcome measures. 

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Data from a hemophilia clinical trial involving the intrahepatic administration of AAV transducing factor 
IX revealed a transient transaminitis followed by decline in the patient’s expression of factor IX 
(Mingozzi & High 2007; Li et al. 2007). The apparent immunological response has been attributed to 
immunodominant epitopes on the AAV capsid although the mechanism of antigen presentation is still 
obscure (Mingozzi et al. 2007). Although the CNS is relatively immunologically privileged, we will 
employ an ELISpot assay to assess T-cell immune responses in the study subjects. 
 
Based on multiple clinical trials using the AAV2 viral vector, no adverse events have been noted, and 
are anticipated. Over 250 patients have received AAV2 for a variety of brain conditions without any 
direct adverse events associated with the vector. Overexpression of the AADC gene, a normal human 
gene, in the context of AADC deficiency may result in dyskinesias (see section below). However, this is 
an anticipated, and transient, event which would be consistent with a functional gene product in the SN, 
and would represent a proof of biological activity. We would treat patients with dyskinesia as needed and 
specified in the clinical protocol. 
 
13.3 Risks of Imaging (MR imaging, PET) 
13.3.1 Risks of MR imaging 
People are at risk for injury from the MR imaging magnet if they have pacemakers or other implanted 
electrical devices, brain stimulators, some types of dental implants, older generation aneurysm clips 
(metal clips on the wall of a large artery), some prostheses (such as heart valves and cochlear implants) 
or shrapnel fragments. Subjects will be screened for these conditions before having any MRI scans. In 
addition, all magnetic objects (such as watches, coins, jewelry, and credit cards) will be removed before 
entering the MRI suite. Any patient treated with a rotigotine patch should have the patch removed prior 
to MRI (patch contains aluminium). Operating room personnel involved in the surgical procedure are 
also screened prior to entering the MRI suite as part of routine safety procedures. 
 
It is not known if MRI is completely safe for a developing fetus. Therefore, all adolescents of 
childbearing potential will have a pregnancy test performed if there is a reasonable chance that they 
could be pregnant at screening. No scanning will be done if the pregnancy test is positive, and subjects 
who are discovered to be pregnant will be excluded from the study. 
 
People with fear of confined spaces may become anxious during MR imaging. As study subjects will be 

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under anesthesia for their imaging procedures, we do not anticipate this problem occurring. Those with 
back problems may have back pain or discomfort from lying in the scanner. The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone having 
a MRI scan, either awake or under anesthesia, will be fitted with hearing protection. 
 
The risks of an IV catheter for administration of contrast (Gadolinium) include bleeding, infection, or 
inflammation of the skin and vein with pain and swelling. Symptoms from the contrast infusion are 
usually mild and may include coldness in the arm during the injection, a metallic taste, headache, and 
nausea. In an extremely small number of patients, more severe symptoms have been reported including 
shortness of breath, wheezing, hives, and lowering of blood pressure. People with kidney disease are at 
risk for a serious reaction to gadolinium contrast called “nephrogenic systemic fibrosis” which has 
resulted in a very small number of deaths. Blood test results will be reviewed for kidney function prior 
to MRI scanning. Subjects will not receive Gadolinium for an MR scan if their kidney function is 
abnormal and it is felt that contrast would pose significant risk to them. 
13.3.2 Risks of PET 
This research study involves exposure to radiation from PET scans for all study subjects. The total 
amount of radiation received in this study is from three injections of [18F] fluoro-L-Dopa (FDOPA) (0.043 
mCi/kg per injection) and from the associated transmission scans with a Cs-137 external source. The 
dose of 0.043mCi/kg for F-DOPA is weight based and will not exceed the dose of 3.0 mCi per injection. 
The UCSF and OSU Radiation Safety Committees have reviewed the use of radiation in this research 
study and has approved this use as involving slightly greater than minimal risk (RU133031-01A), but is 
regarded as necessary to obtain the research information desired. 
 
Subjects in this study will receive 3 scans over about 24 months. Although each organ will receive a 
different dose, the total amount of radiation exposure received from these procedures is equal to a 
uniform whole-body exposure of 12 mSv. This is equivalent to 4 times the yearly natural background of 
radiation in the US (3 mSv). 
 
If any of the subjects undergoing PET scanning is a female of child-bearing potential, pregnancy testing 
will be performed (and must be negative) prior to each PET scan. 
13.3.3 Risks of DAT SPECT 

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This research study involves exposure to radiation. DaTscan™ Ioflupane I-123 is a radiopharmaceutical 
agent that emits a small amount of radiation and is used to image the neurons that transport dopamine 
within the striatum. The UCSF and OSU Radiation Safety Committees have reviewed the use of radiation 
in this research study and has approved this use as involving slightly greater than minimal risk, but is 
regarded as necessary to obtain the research information desired. 
 
Subjects in this study will receive DaTscan™ Ioflupane I-123 on SPECT scan during the baseline period. 
The dose of radioactive ligand will be calculated based on patient weight. Assuming a total dose of 185 
mBq, individual organs will receive a different dose of radiation: 53 μGy to the urinary bladder wall, 9.2 
μGy to blood-forming organs (e.g. marrow), 16.8 μGy to the ovaries, 8.5 μGy to the testes, and 17.8 μGy 
to the brain. The total amount of radiation exposure received from these procedures is equal to a uniform 
whole-body exposure of 3.9 mSv. This is equivalent to 1.3 times the yearly natural background of 
radiation in the US (3 mSv). As noted above in section 8.4.3, the DaTscan injection may contain up to 
6% of free iodide (iodine-123). To decrease thyroid accumulation of iodine-123, a dose up to 100 mg of 
Potassium Iodide Oral Solution or Lugol's Solution will be administered. If any of the subjects undergoing 
DAT SPECT scanning is a female of child-bearing potential, pregnancy testing will be performed (and 
must be negative) prior to each scan. 
 
13.4 Risks of Blood Samples 
The risk of blood drawing includes a bruise at the needle insertion site and possible fainting. 
 
13.5 Risks of Sedation 
The risks associated with having sedation include: dizziness, drowsiness, allergic reaction, tiredness, 
weakness and the rare possibility of dry mouth. 
 
Patients with AADC deficiency have an increased risk of hypoglycemia, hypotension, and bradycardia 
during periods of physiological stress due to their peripheral catecholamine deficiency. 
 
13.6 Post-therapy Dyskinesia 
Gene transfer is expected to result in an increase in brain dopamine production within approximately one 
month after surgery. One anticipated effect of the increase in dopamine is the occurrence of involuntary 
jerky or writhing movements (dyskinesia). Subjects will be monitored frequently for the emergence of 

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dyskinesia in the 2 months after gene transfer, and the clinical course will be followed closely and 
documented via serial video examinations. Refer to section 7.4.6 for further information. Guidelines for 
the management of post-treatment dyskinesia are in Appendix 9. 
 
13.7 Behavioral Adverse Effects 
Increased dopamine in mesocortical and mesolimbic circuits has the potential to cause behavioral effects 
such as agitation, vivid dreams, hallucinations, and compulsive behaviors. We will monitor subjects 
closely at each visit for changes in behavior or sleep that may be subtle indicators of such effects. If 
behavioral adverse effects occur, treatment should be promptly initiated. If the subject has co-existing 
dyskinesias requiring treatment with tetrabenazine, then this should be the first step (following protocol 
above) as behavioral symptoms may respond to the same treatment. If tetrabenazine is not required for 
treatment of dyskinesias, then treatment with quetiapine should be started, beginning at a low dose (6.25- 
12.5 mg daily) and increasing gradually while monitoring for adverse effects including hypotension. 
 
14 SUBJECT SAFETY MONITORING 
 
There will be ongoing extensive caregiver education before and after surgery to ensure that the caregiver 
reports all adverse events at the time they occur. All personnel involved in this study are provided with 
training and written guidelines concerning the definitions of adverse events (AE) and serious adverse 
events (SAE) and their responsibilities if they believe they have identified an AE/SAE, including 
reporting any SAE within 24 hours and the completion of the AE/SAE Form. 
 
Monitoring of safety of individual subjects during study procedures will be performed by the medical 
staff and the research nurses. Safety assessments include: co-infusion of gadoteridol with AAV2- 
hAADC to confirm dosing to appropriate region, intra-operative and post-operative MRI, grading of 
adverse events, physical examinations, clinical laboratory analysis (hematology, clinical chemistries, 
immunologic assessments). 
 
Adverse effects will be monitored systematically throughout the study with formal assessments at each 
evaluation visit. In addition, subjects will be encouraged to contact the investigators by telephone any 
time there is concern about side effects. If necessary, an unscheduled clinical visit with the investigator 
will be arranged. Subjects will have access to clinicians day and night for the duration of the study. The 
Principal Investigator, in collaboration with the Data and Safety Monitoring Board, will be responsible 

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for monitoring data collected to ensure the safety of subjects. 
 
14.1 Toxicity Criteria 
Toxicities and adverse events will be recorded and categorized according to severity, relationship to 
procedure, and relationship to the study procedure or study drug. Toxicity criteria are based on the NCI 
CTCAE version 4.0. The scale can be accessed at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
 
14.2 Criteria for Individual Subject Withdrawal 
The subject may be withdrawn from the study at any time for the following reasons: 
 
1. The subject’s parents/Durable Power of Attorney desires to discontinue participation in 
this study. 
2. Investigator’s prerogative. The subject is unwilling or unable to comply with the 
protocol. 
 
15 OUTCOME MEASURES 
 
Initial outcome measures will be determined after all subjects in each cohort have reached one year after 
surgery. Follow-up analysis will be performed after all subjects have reached 2 years after surgery. A 
second longer-term clinical follow-up study of all subjects will occur for 5 years to obtain additional 
longitudinal outcome data for safety and efficacy measures. 
 
15.1 Primary Outcome Measures 
Safety: 
• Assessment of AE or SAE and its relationship to study surgery, infusion, or 
treatment effect (graded as definite, probable, possible, unlikely or unrelated) 
 
Biological Activity: 
• Effective improvement of AADC function by assays of CSF neurotransmitter 
metabolites and PET imaging. 
• Improvements in motor function and reduction of neurological symptoms as 

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measures of clinical efficacy resulting from AAV2-hAADC treatment. 
 
15.2 Secondary Outcome Measures 
• GMFM-88 
• Oculogyric Crisis Log 
• PEDI-CAT 
• PedsQL 
• Behavior Diary 
 
16 SAMPLE SIZE CALCULATIONS AND DATA ANALYSIS 
 
This is an open-label safety study that has not been designed as a powered efficacy study. Statistical 
analysis will be performed on quantifiable measures of clinical responses to treatment by comparing pre- 
and post-operative assessments, and analyzing any differences between the dose cohorts. 
16.1 Sample Size 
 
The number of subjects is based on the desire to gain adequate safety and preliminary clinical outcome 
information to support future work. Inferential statistical hypothesis testing is not the primary intent of 
the study. It is judged that the selected sample size, based on previous animal experience and empiric 
criteria, will provide acceptable clinical validity for the study objectives. 
Previous Phase 1 studies involving innovative surgical and medical interventions for rare CNS disorders 
have historically enrolled similar numbers of subjects. 
16.2 Data Analysis 
 
Analysis of the study data will primarily be tabular, graphical and descriptive, with a view to elucidating 
the time course and pattern of responses to AAV2-hAADC treatment and thoroughly exploring the 
antecedents of any observed adverse effects of therapy. Particular attention will be paid to verifying that 
all subjects enrolled satisfy the stated inclusion criteria, and on checking for any protocol violations. 
Statistical analysis will be performed on quantifiable measures of clinical responses to treatment by 
comparing pre- and post-operative assessments, and analyzing any differences between the two dose 
cohorts. 
Characteristics of the surgical procedure such as accuracy of cannula placement, number of cannula 

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passes, any events during infusion such as reflux or non-targeted delivery will be analyzed. Coverage of 
target structures will be measured on the MR images acquired during the CED procedure. Calculations will 
be made of the total volume of gadoteridol distribution, percentage covered by gadoteridol, and 
percentage of gadoteridol distribution contained within the target structures. 
16.3 Safety Analysis 
 
Safety data will be summarized for the total study population and the pooled safety data will be further 
broken down by the dose level. The disposition of the patients will be summarized by tabulating the 
number of screened, completed, and discontinued patients. The reasons for premature discontinuations 
will be tabulated. The extent of exposure to the study treatment will be summarized by tabulating the 
number of patients being exposed to each dose level. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. 
The treatment-emergent AEs (TEAEs), i.e., events which start or worsen during the study treatment will 
be summarized by body system and preferred term. In addition, separate summaries will be provided for 
TEAEs by severity and relationship to study drug, as well as adverse events leading to study drug 
discontinuation and serious adverse events. The tolerability will be assessed by number of patients 
having DLTs and with premature discontinuations of study treatment. 
The other safety analyses include the evaluation of safety laboratory tests, vital signs and brain imaging. 
The safety laboratory tests and vital signs will be evaluated by summarizing the changes from baseline 
with descriptive statistics and by tabulating the number of patients with abnormal values. The evaluation 
of the brain imaging is based on post-operative MRI and/or computed tomography (CT) (with contrast 
if clinically indicated) findings. 
16.4 Efficacy Analysis 
For the evaluation of the efficacy, there will be two primary clinical outcome measures: 
• Motor Function, as assessed by the Gross Motor Function Measure (GMFM-88). The total score 
will be derived as an unweighted average of the 5 dimension scores: lying and rolling (17 items); 
sitting (20 items); crawling and kneeling (14 items); standing (13 items) and walking, running, 
and jumping (24 items). Each dimension score will be defined as % of maximum score for the 
dimension in question. 
• Frequency of motor behaviors, as measured by a Oculogyric Crisis Log: each recorded episode 

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will be classified as mild, moderate or severe. The area under the curve (AUC) of the diary 
symptoms will be used as the endpoint. The AUC will be calculated for each study month as a 
sum of duration of symptoms (hours) multiplied by the severity (0-3) of the symptom in question. 
The endpoint is the change from baseline (average of 3 months preceding the baseline) to 1 year 
(average of 3 months preceding the visit at Month 12). 
 
The secondary analyses of the primary endpoints include the evaluation of the data at time points other 
than 1 year. In addition, the following endpoints will be evaluated as secondary analyses: 
• Evaluation of each of the 5 GMFM-88 dimension scores separately. 
• Evaluation of the OGC Log as total number of episodes, total duration of episodes and 
distribution of the severity scores. 
 
All data collected during the study will be used for the evaluation of the clinical outcome measures. The 
evaluation will be focused on the following comparisons: 
• Change from baseline to one year in all patients treated with the selected dose level (primary 
comparison). However, if no dose-response is seen, both dose levels will be included in the 
primary comparison. 
• Difference in change from baseline to one year between the patients treated with the selected 
dose level and the other dose level used. 
 
In addition to the comparisons defined above, efforts will be made to compare the changes seen in the 
present study to natural progression of the disease as assessed in The Natural History of Symptoms and 
Motor Function in the AADC Deficiency Study, a related external study at Washington University in St. 
Louis, led by Dr. Toni Pearson,. These comparisons may involve comparison of the changes between the 
treated patients from the present study and untreated patients, using endpoints derived from the elements 
of the primary outcome measures. The definition and analysis of these endpoints will depend on the 
availability of the data collected from The Natural History Study. 
 
17 HUMAN SUBJECTS PROTECTION 
 
17.1 Human Subjects Involvement and Characteristics 

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This protocol, advertisements (if applicable) and/or web-based information, written information to be 
provided to subjects’ families, and stipends will be reviewed and approved by the study site Human 
Subjects Committee/IRB prior to enrollment of subjects in the study. A signed consent form will be 
obtained from parents/guardians of each subject. The consent form will describe the purpose of the 
study, the procedures to be followed, and the risks and benefits of participation. A copy of the consent 
form will be given to the parents, or legal guardian, and this fact will be documented in the subject’s 
record. Any revisions to the above-mentioned documents will also be submitted for review. 
 
17.2 Adequacy of Protection Against Risks 
There will be ongoing extensive caregiver education before and after surgery to ensure that the caregivers 
report all adverse events at the time they occur. All personnel involved in this study are provided with 
training and written guidelines concerning the definitions of adverse events (AE) and serious adverse 
events (SAE) and their responsibilities if they believe they have identified an AE/SAE, including 
reporting any SAE within 24 hours and the completion of the AE/SAE form. 
 
Adverse events will be monitored systematically throughout the study with formal assessments at each 
evaluation visit. In addition, subjects will be encouraged to contact the investigators by telephone any 
time there is concern about side effects. If necessary, an unscheduled clinical visit with the investigator 
will be arranged. Subjects will have access to clinicians day and night for the duration of the study. The 
Investigators, in collaboration with the Data and Safety Monitoring Board, will be responsible for 
monitoring data collected to ensure the safety of subjects. Confidential identification codes will be used 
on all study data forms. Should results of the study be published or reported, individual names or other 
identifying information will not be used. 
 
Treatment intervals between subjects have been set at a minimum observation period of 90 days between 
each treated subject and the next subject within the first group of 3 subjects. This will provide time to 
identify serious safety or tolerability problems that might arise. 
 
All reasonable and appropriate activities will be employed to try to prevent adverse events and to 
minimize the consequences of any that do occur. 
 
17.3 Safeguards for Vulnerable Populations 

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Children with AADC have limited capacity to understand the nature of their condition or the proposed 
treatment. Therefore, both parent(s)/guardian(s) will be asked to give their permission for their child to 
participate in the clinical study. We will request that the IRB waive the requirement for assent in this 
situation where the child is not capable of assent given his cognitive and emotional maturity. 
Gaining informed consent from parent(s)/guardian(s) will be an ongoing/iterative process. 
Parent(s)/guardian(s) will have ample time to review the study information and consent form on the 
website should they have interest in participation in the study. Initial consent will be obtained prior to 
screening procedures. After screening, should the subject be eligible, parent(s)/guardian(s) will be asked 
to sign the consent form indicating their desire to move forward to the treatment phase. 
 
Should any new information become available during the study that might affects the decision to 
continue participation, parent(s)/guardian(s) will be contacted to discuss that information and further 
provide consent should they wish to continue. 
 
Investigators and study personnel are sensitive of the influence of therapeutic misconception about 
participation in the study. The informed consent has been designed to appropriately indicate that the 
treatment is experimental, and that no direct benefit is expected. 
 
Parents will be provided with additional resources available on NIH and FDA Website to help them 
through the decision making process. 
 
• NIH Website — Children and Clinical Studies: 
http://www.nhlbi.nih.gov/childrenandclinicalstudies/index.phphttp://www.nhlbi.nih.gov/childre 
nandclinicalstudies/index.php 
 
• FDA Website — Should your child be in a clinical trial? 
http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm048699.htm 
 
Families will also have visits with a Social Worker as part of the informed consent process and as needed 
or requested throughout the study duration. During these visits, families can discuss any issues they 
might not feel comfortable with discussing with the study personnel. The Social Worker will also make 
recommendations for further evaluation if any of the family members need additional support. 
 
 

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18 ANTICIPATED BENEFITS 
 
18.1 Potential Benefits to Subjects and Others 
Subjects in this study will have disabling symptoms that remain refractory to currently available 
medication therapies. Subjects may experience an improvement in symptoms after experimental therapy. 
Complications caused by their primary condition may progress more slowly than the natural course. We 
feel that the potential risks to our disabled and treatment-refractory subjects are reasonable in relation to 
the possible benefits of experimental therapy. 
 
18.2 Importance of the Knowledge to be Gained 
A careful, systematic scientific evaluation of the safety, tolerability and eventually the clinical effects of 
AADC gene transfer in AADC deficiency are scientifically rational and could lead to a breakthrough in 
disease-modifying therapy. 
 
19 CLASSIFICATION OF RISK 
 
Subjects may receive a direct benefit from participation in this study. There is greater than minimal risk 
for all subjects in the study, but because of the possible benefit, the risks are reasonable. 
 
20 CONSENT DOCUMENTS AND PROCESS 
A copy of the informed consent form will be provided to the parent(s)/guardian(s) of potential study 
subjects. Parent(s)/guardian(s)will be encouraged to review it with relatives, friends or their primary care 
physician and be prepared for the face-to-face meetings with the study team. 
 
As part of the informed consent process, parent(s)/guardian(s) will be informed about the most likely 
possible adverse effects of the operation to infuse the viral vectors. These include stroke, bleeding or 
infection. Parent(s)/guardian(s) will be informed about the potential side effects of viral vector delivery 
such as immunological reactions. They will be informed about the most common side effects reported 
in prior studies of AAV2-hAADC. Parent(s)/guardian(s) will be informed that AADC gene expression 
cannot be regulated and potential consequences of excessive dopaminergic function will be described, 
including dyskinesias, confusion, psychosis and impulse control disorders. As with other stereotactic 
brain procedures, there could be alterations in mood or cognitive functions. More information about 
potential adverse experiences is provided above in the section on Safety Monitoring. 

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Informed consent will be obtained after meetings involving parent(s)/guardian(s), the study coordinator 
and the study neurologist and neurosurgeon. The informed consent document will be reviewed in detail 
and there will be an opportunity to answer any questions or clarify any issues. The parent(s)/guardian(s) 
of the subject will provide consent by signing the informed consent document. One signed copy of the 
consent form will be provided to the parent(s)/guardian(s) and the original will be kept on file. A standard 
operative consent will also be obtained by the study neurosurgeon prior to actual procedure. 
 
A copy of the blank Informed Consent document is provided separately. 
 
21 DATA AND SAFETY MONITORING 
 
The Principal Investigator will provide overall supervision of the study and review the data on a monthly 
basis. The data will be presented and reviewed by the Data and Safety Monitoring Board (DSMB) 
approximately 90 days after completion of treatment of every 3rd    subject and as needed. Data will be 
presented and reviewed by the study site IRB annually in conjunction with the Continuing Review. 
 
21.1 Data and Safety Monitoring Board, Medical Monitor and Advisory Committee 
The study will incorporate oversight by a Medical Monitor, a Data Safety Monitoring Board, and an 
Advisory Committee to assess the safety data for each subject before proceeding with the next subject, 
as well as prior to dose escalation. 
 
The roles and responsibilities of the DSMB will be described in detail in the DSMB charter. Briefly, the 
primary charge of the DSMB will be to monitor safety and the occurrence of the following: 
 
1. Serious adverse events (SAEs) 
 
2. Deaths (also reported as SAEs) 
 
3. All other adverse events (AEs) 
 
4. Premature withdrawal of research participants from the study 
 
5. Dose Limiting Toxicity. 
 
6. Stopping Rules (see below). 
 
The DSMB may meet in person or through a teleconference. Reports summarizing study progress, SAEs 

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and enrollment will be sent to the DSMB by the study coordinator every 6 months, at least one week prior 
to the scheduled DSMB meeting. Information in the reports should be current as of one month prior to 
the date of the DSMB meeting. The DSMB will also be available to discuss ad hoc (at the request of the 
Sponsor, Principal Investigator or Medical Monitor) any concerns or events during the course of the 
study. Unscheduled DSMB meetings may be called as necessary by the DSMB. 
 
The Medical Monitor, who is not on the study team, is Dr. Erika Augustine (University of Rochester), a 
pediatric neurologist who is a movement disorders specialist. Her role will be to regularly review all 
safety data and adverse events, and provide an objective opinion regarding clinical outcomes and adverse 
events, which she will communicate to the study PI and DSMB. 
 
The Advisory Committee (AC) will consist of 6 individuals who will directly with the PI and study team 
to provide overall scientific oversight for the study. The role of the AC will be to provide overall 
oversight regarding the interpretation of the results, review possible changes in the protocol resulting 
from obtained data, and to assess safety data. The AC will provide scientific guidance and advice to the 
PI and study team as required. The AC will meet either in person or by teleconference ad hoc as data 
becomes available for review. . The members of the AC are: 
 
Ron Crystal - Professor and Chairman, Department of Genetic Medicine at Weill Cornell Medical 
College, New York, NY 
 
Darryl De Vivo - Sidney Carter Professor of Neurology, Professor of Pediatrics, and Director 
Emeritus (1979-2000) of the Pediatric Neurology Service at Columbia University Medical 
Center, New York, NY 
Jonathan Mink - Frederick A. Horner, MD Endowed Professor in Pediatric Neurology, Professor 
of Neurology, Neuroscience, and Pediatrics, Chief, Division of Child Neurology, Vice Chair, 
Department of Neurology, University of Rochester Medical Center, Rochester, NY 
 
Un Kang - H. Houston Merritt Professor of Neurology and Chief of the Division of Movement 
Disorders at Columbia University, New York, NY 
 
Roser Pons - Assistant Professor, First Pediatric Clinic, Medical School, National and 
Kapodistrian University of Athens, Agia Sofia Hospital, Athens, Greece 

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Manju Kurian - Professor of Neurogenetics, Developmental Neurosciences Department, 
University College London, Great Ormond Street Institute of Child Health, London, England 
 
21.2 Dose Limiting Toxicity 
Dose-limiting toxicity will be defined as any Grade 3 or 4 toxicity (NCI CTCAE v.4) that is thought to 
be possibly or probably related to AAV2-hAADC. 
 
If none of the subjects in the first group experiences a Dose Limiting Toxicity (DLT), dose escalation 
may proceed and subjects may be enrolled in the higher dose level group. Should 2 or more subjects in 
any group experience DLT as defined above, the study will be stopped pending review and discussion 
with FDA. 
 
21.3 Stopping Rules 
The occurrence of any of the following events (regardless of suspected causal associations) during or 
after the administration of AAV2-hAADC would result in the halting of study enrollment and 
notification of the DSMB, FDA, and IRB: 
 
• Any significant procedural deviation or violations, e.g. dosing error, equipment failure 
 
• Any symptomatic intra-cerebral hemorrhage or stroke 
 
• Any central nervous system infections 
 
• Dyskinesia severe enough to require ICU admission for greater than 30 days 
 
• Any death 
 
Once a stopping rule is reached, the trial would be suspended (i.e., cessation of AAV2-hAADC 
administration to any subjects) pending a comprehensive safety review by the DSMB. Triggering of any 
Stopping Rule will prompt notification to FDA, IRB, NIH Office of Biotechnology, and the Institutional 
Biosafety Committee (IBC). 
 
Additional Stopping Rules may be developed if unexpected serious adverse events (SAE) with causal 
relationship to AAV2-hAADC, including delivery procedure, appear during the study. 
 

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22 QUALITY ASSURANCE 
 
A Study Management Service (SMS) will provide monitoring for this study. The expected level of 
monitoring will be 2 subjects longitudinally, i.e., monitored throughout the study, plus random 
monitoring of 1 or 2 randomly selected subjects, depending on whether 6 or less, or 7 or more subjects 
have been enrolled, respectively. Subject monitoring will be by comparison of individual subject records 
and other source documents with case report forms (CRFs). In addition, critical information will be 
monitored 100%. Critical information includes but is not limited to IRB approvals and correspondence, 
subject tracking and eligibility, informed consent, drug accountability and storage, and adverse event 
reporting. 
 
23 ADVERSE EVENT AND UNANTICIPATED PROBLEM REPORTING 
 
Adverse events (AEs) will be collected from the establishment of baseline conditions (admission) 
through 36 months following study drug administration. “Adverse Events” and “Serious Adverse 
Events”, the determination of the relatedness to the investigational treatment, and reporting will follow 
the definitions and reporting requirements mandated in 21CFR 312.32. 
Serious or unexpected adverse events and other unanticipated problems related to the research aspects 
of the protocol will be submitted to the study site IRB/Committee on Human Research (CHR) within 10 
working days of PI awareness. Expected or non-serious adverse events will be reported at the time of 
continuing review. 
 
24 ALTERNATIVES TO PARTICIPATION 
 
In addition to participation in this clinical study, there may be other investigational studies for which 
these patients may qualify. 
 
25 CONFIDENTIALITY 
 
Information about study subjects will be handled as confidentially as possible to the extent permitted by 
applicable laws and/or regulations. Data and blood samples will be coded and stored in cabinets. Blood 
samples sent to outside labs will be labeled with a code number assigned by the Principal Investigator or 
clinical study coordinator. 
 

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26 CONFLICT OF INTEREST 
 
The Sponsor, Krystof Bankiewicz MD, PhD, is an inventor on patents held by the Regents of the 
University of California covering AAV delivery to the brain. 
 
27 TECHNOLOGY TRANSFER 
 
1. MRI Interventions Inc. 
 
SmartFlow®      Cannula and ClearPoint®      neuro-navigational  devices  will  be  provided  by  MRI 
Interventions Inc. under a collaborative research agreement. 
2. Children’s Hospital of Philadelphia 
 
AAV2-hAADC was manufactured and provided by Children's Hospital of Philadelphia. 
 
28 RESEARCH AND TRAVEL COMPENSATION 
 
Subjects will not be paid for participation in this protocol. However, meals, parking, and lodging costs 
will be paid for . All airfare for subjects and caregivers for visits will be booked in advance by the study 
coordinator. The study site will also coordinate and pay for in-town transport. 
 
 
 

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29 REFERENCES 
 
Brun, L., L. H. Ngu, W. T. Keng, G. S. Ch'ng, Y. S. Choy, W. L. Hwu, W. T. Lee, M. A. Willemsen, M. 
M. Verbeek, T. Wassenberg, L. Regal, S. Orcesi, D. Tonduti, P. Accorsi, H. Testard, J. E. 
Abdenur, S. Tay, G. F. Allen, S. Heales, I. Kern, M. Kato, A. Burlina, C. Manegold, G. F. 
Hoffmann and N. Blau (2010). "Clinical and biochemical features of aromatic L-amino acid 
decarboxylase deficiency." Neurology 75(1): 64-71 PMCID: 
Caviness, V. S., Jr., D. N. Kennedy, C. Richelme, J. Rademacher and P. A. Filipek (1996). "The human 
brain age 7-11 years: a volumetric analysis based on magnetic resonance images." Cereb Cortex 
6(5): 726-736 PMCID: 
Christine, C. W., P. A. Starr, P. S. Larson, J. L. Eberling, W. J. Jagust, R. A. Hawkins, H. F. VanBrocklin, 
J. F. Wright, K. S. Bankiewicz and M. J. Aminoff (2009). "Safety and tolerability of putaminal 
AADC gene therapy for Parkinson disease." Neurology 73(20): 1662-1669 PMCID: 
Dumas, H. M. and M. A. Fragala-Pinkham (2012). "Concurrent validity and reliability of the pediatric 
evaluation of disability inventory-computer adaptive test mobility domain." Pediatr Phys Ther 
24(2): 171-176; discussion 176 PMCID: 
Dumas, H. M., M. A. Fragala-Pinkham, S. M. Haley, P. Ni, W. Coster, J. M. Kramer, Y. C. Kao, R. 
Moed and L. H. Ludlow (2012). "Computer adaptive test performance in children with and 
without disabilities: prospective field study of the PEDI-CAT." Disabil Rehabil 34(5): 393-401 
PMCID: 3668545 
Eapen, M., D. H. Zald, J. C. Gatenby, Z. Ding and J. C. Gore (2011). "Using high-resolution MR imaging 
at 7T to evaluate the anatomy of the midbrain dopaminergic system." AJNR Am J Neuroradiol 
32(4): 688-694 PMCID: 3076524 
Fiandaca, M. S., V. Varenika, J. Eberling, T. McKnight, J. Bringas, P. Pivirotto, J. Beyer, P. Hadaczek, 
W. Bowers, J. Park, H. Federoff, J. Forsayeth and K. S. Bankiewicz (2009). "Real-time MR 
imaging of adeno-associated viral vector delivery to the primate brain." Neuroimage 47 Suppl 2: 
T27-35 PMCID: PMC2719019 
Gill, S. S., N. K. Patel, G. R. Hotton, K. O'Sullivan, R. McCarter, M. Bunnage, D. J. Brooks, C. N. 
Svendsen and P. Heywood (2003). "Direct brain infusion of glial cell line-derived neurotrophic 
factor in Parkinson disease." Nat Med 9(5): 589-595 PMCID: 
Haley, S., W. Coster, L. Ludlow, J. Haltiwanger and A. PA (1992). Pediatric Evaluation of Disability 
Inventory: Development, Standardization and Administration Manual. Boston, MA, Trustees of 
Boston University. 
Hnasko, T. S., F. A. Perez, A. D. Scouras, E. A. Stoll, S. D. Gale, S. Luquet, P. E. Phillips, E. J. Kremer 
and R. D. Palmiter (2006). "Cre recombinase-mediated restoration of nigrostriatal dopamine in 
dopamine-deficient mice reverses hypophagia and bradykinesia." Proc Natl Acad Sci U S A 
103(23): 8858-8863 PMCID: 1466546 
Hwu, W. L., S. Muramatsu, S. H. Tseng, K. Y. Tzen, N. C. Lee, Y. H. Chien, R. O. Snyder, B. J. Byrne, 
C. H. Tai and R. M. Wu (2012). "Gene therapy for aromatic L-amino acid decarboxylase 
deficiency." Sci Transl Med 4(134): 134ra161 PMCID: 
Hyland, K. and P. T. Clayton (1990). "Aromatic amino acid decarboxylase deficiency in twins." J Inherit 
Metab Dis 13(3): 301-304 PMCID: 
Hyland, K. and P. T. Clayton (1992). "Aromatic L-amino acid decarboxylase deficiency: diagnostic 
methodology." Clin Chem 38(12): 2405-2410 PMCID: 
Hyland, K., R. A. Surtees, C. Rodeck and P. T. Clayton (1992). "Aromatic L-amino acid decarboxylase 
deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter 

AAV2-hAADC / Primary AADC Deficiency 
Bankiewicz / OSU 
Version 14.0 
Page 76 of 78 
August 3, 2020 
 
 
amine synthesis." Neurology 42(10): 1980-1988 PMCID: 
Jernigan, T. L., S. L. Archibald, M. T. Berhow, E. R. Sowell, D. S. Foster and J. R. Hesselink (1991). 
"Cerebral structure on MRI, Part I: Localization of age-related changes." Biol Psychiatry 29(1): 
55-67 PMCID: 
Jernigan, T. L. and P. Tallal (1990). "Late childhood changes in brain morphology observable with 
MRI." Dev Med Child Neurol 32(5): 379-385 PMCID: 
Johnston, L. C., J. Eberling, P. Pivirotto, P. Hadaczek, H. J. Federoff, J. Forsayeth and K. S. Bankiewicz 
(2009). "Clinically relevant effects of convection-enhanced delivery of AAV2-GDNF on the 
dopaminergic nigrostriatal pathway in aged rhesus monkeys." Hum Gene Ther 20(5): 497-510 
PMCID: 19203243 
Kells, A. P., J. Forsayeth and K. S. Bankiewicz (2012). "Glial-derived neurotrophic factor gene transfer 
for Parkinson's disease: anterograde distribution of AAV2 vectors in the primate brain." 
Neurobiol Dis 48(2): 228-235 PMCID: 3289735 
Kim, D. S., R. D. Palmiter, A. Cummins and C. R. Gerfen (2006). "Reversal of supersensitive striatal 
dopamine D1 receptor signaling and extracellular signal-regulated kinase activity in dopamine- 
deficient mice." Neuroscience 137(4): 1381-1388 PMCID: 
Laske, D. W., P. F. Morrison, D. M. Lieberman, M. E. Corthesy, J. C. Reynolds, P. A. Stewart-Henney, 
S. S. Koong, A. Cummins, C. H. Paik and E. H. Oldfield (1997a). "Chronic interstitial infusion 
of protein to primate brain: determination of drug distribution and clearance with single-photon 
emission computerized tomography imaging." J Neurosurg 87(4): 586-594 PMCID: 
Laske, D. W., R. J. Youle and E. H. Oldfield (1997b). "Tumor regression with regional distribution of 
the targeted toxin TF-CRM107 in patients with malignant brain tumors." Nat Med 3(12): 1362- 
1368 PMCID: 
Lee, H. F., C. R. Tsai, C. S. Chi, T. M. Chang and H. J. Lee (2009). "Aromatic L-amino acid 
decarboxylase deficiency in Taiwan." Eur J Paediatr Neurol 13(2): 135-140 PMCID: 
Lonser, R. R., R. Schiffman, R. A. Robison, J. A. Butman, Z. Quezado, M. L. Walker, P. F. Morrison, 
S. Walbridge, G. J. Murray, D. M. Park, R. O. Brady and E. H. Oldfield (2007a). "Image-guided, 
direct convective delivery of glucocerebrosidase for neuronopathic Gaucher disease." Neurology 
68(4): 254-261 PMCID: 
Lonser, R. R., S. Walbridge, K. Garmestani, J. A. Butman, H. A. Walters, A. O. Vortmeyer, P. F. 
Morrison, M. W. Brechbiel and E. H. Oldfield (2002). "Successful and safe perfusion of the 
primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during 
infusion." J Neurosurg 97(4): 905-913 PMCID: 
Lonser, R. R., K. E. Warren, J. A. Butman, Z. Quezado, R. A. Robison, S. Walbridge, R. Schiffman, M. 
Merrill, M. L. Walker, D. M. Park, D. Croteau, R. O. Brady and E. H. Oldfield (2007b). "Real- 
time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note." J 
Neurosurg 107(1): 190-197 PMCID: 
Lumsden, D. E., C. Lundy, C. Fairhurst and J. P. Lin (2013). "Dystonia Severity Action Plan: a simple 
grading system for medical severity of status dystonicus and life-threatening dystonia." Dev Med 
Child Neurol 55(7): 671-672 PMCID: 
Manegold, C., G. F. Hoffmann, I. Degen, H. Ikonomidou, A. Knust, M. W. Laass, M. Pritsch, E. 
Wilichowski and F. Horster (2009). "Aromatic L-amino acid decarboxylase deficiency: clinical 
features, drug therapy and follow-up." J Inherit Metab Dis 32(3): 371-380 PMCID: 
Mingozzi, F., N. C. Hasbrouck, E. Basner-Tschakarjan, S. A. Edmonson, D. J. Hui, D. E. Sabatino, S. 
Zhou, J. F. Wright, H. Jiang, G. F. Pierce, V. R. Arruda and K. A. High (2007). "Modulation of 
tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer 

AAV2-hAADC / Primary AADC Deficiency 
Bankiewicz / OSU 
Version 14.0 
Page 77 of 78 
August 3, 2020 
 
 
to liver." Blood 110(7): 2334-2341 PMCID: 1988950 
Muramatsu, S., K. Fujimoto, S. Kato, H. Mizukami, S. Asari, K. Ikeguchi, T. Kawakami, M. Urabe, A. 
Kume, T. Sato, E. Watanabe, K. Ozawa and I. Nakano (2010). "A phase I study of aromatic L- 
amino acid decarboxylase gene therapy for Parkinson's disease." Mol Ther 18(9): 1731-1735 
PMCID: 2956925 
Peden, C. S., C. Burger, N. Muzyczka and R. J. Mandel (2004). "Circulating anti-wild-type adeno- 
associated virus type 2 (AAV2) antibodies inhibit recombinant AAV2 (rAAV2)-mediated, but 
not rAAV5-mediated, gene transfer in the brain." J Virol 78(12): 6344-6359 PMCID: 
Peden, C. S., F. P. Manfredsson, S. K. Reimsnider, A. E. Poirier, C. Burger, N. Muzyczka and R. J. 
Mandel (2009). "Striatal readministration of rAAV vectors reveals an immune response against 
AAV2 capsids that can be circumvented." Mol Ther 17(3): 524-537 PMCID: 
Pfefferbaum, A., D. H. Mathalon, E. V. Sullivan, J. M. Rawles, R. B. Zipursky and K. O. Lim (1994). 
"A quantitative magnetic resonance imaging study of changes in brain morphology from infancy 
to late adulthood." Arch Neurol 51(9): 874-887 PMCID: 
Pons, R., D. Syrengelas, S. Youroukos, I. Orfanou, A. Dinopoulos, B. Cormand, A. Ormazabal, A. 
Garzia-Cazorla, M. Serrano and R. Artuch (2013). "Levodopa-induced dyskinesias in tyrosine 
hydroxylase deficiency." Mov Disord 28(8): 1058-1063 PMCID: 
Richardson, R. M., F. Gimenez, E. A. Salegio, X. Su, J. Bringas, M. S. Berger and K. S. Bankiewicz 
(2011a). "T2 imaging in monitoring of intraparenchymal real-time convection-enhanced 
delivery." Neurosurgery 69(1): 154-163; discussion 163 PMCID: 
Richardson, R. M., A. P. Kells, A. J. Martin, P. S. Larson, P. A. Starr, P. G. Piferi, G. Bates, L. Tansey, 
K. H. Rosenbluth, J. R. Bringas, M. S. Berger and K. S. Bankiewicz (2011b). "Novel platform 
for MRI-guided convection-enhanced delivery of therapeutics: preclinical validation in 
nonhuman primate brain." Stereotact Funct Neurosurg 89(3): 141-151 PMCID: 3085040 
Richardson, R. M., A. P. Kells, K. H. Rosenbluth, E. A. Salegio, M. S. Fiandaca, P. S. Larson, P. A. 
Starr, A. J. Martin, R. R. Lonser, H. J. Federoff, J. R. Forsayeth and K. S. Bankiewicz (2011c). 
"Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in 
Parkinson's disease." Mol Ther 19(6): 1048-1057 PMCID: 3129792 
Russell, D. J., P. L. Rosenbaum, L. M. Avery and M. Lane (2002). The Gross Motor Function Measure 
(GMFM-66 & GMFM-88) User's Manual. London, Mac Keith Press. 
Salegio, E. A., H. Streeter, N. Dube, P. Hadaczek, L. Samaranch, A. P. Kells, W. San Sebastian, Y. Zhai, 
J. Bringas, T. Xu, J. Forsayeth and K. S. Bankiewicz (2014). "Distribution of nanoparticles 
throughout the cerebral cortex of rodents and non-human primates: Implications for gene and 
drug therapy." Front Neuroanat 8: 9 PMCID: 3956368 
Sanftner, L. M., B. M. Suzuki, M. M. Doroudchi, L. Feng, A. McClelland, J. R. Forsayeth and J. 
Cunningham (2004). "Striatal delivery of rAAV-hAADC to rats with preexisting immunity to 
AAV." Mol Ther 9(3): 403-409 PMCID: 
Su, X., A. P. Kells, E. A. Aguilar Salegio, R. M. Richardson, P. Hadaczek, J. Beyer, J. Bringas, P. 
Pivirotto, J. Forsayeth and K. S. Bankiewicz (2010). "Real-time MR imaging with Gadoteridol 
predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors." Mol 
Ther 18(8): 1490-1495 PMCID: 2927064 
Swoboda, K. J., K. Hyland, D. S. Goldstein, K. C. Kuban, L. A. Arnold, C. S. Holmes and H. L. Levy 
(1999). "Clinical and therapeutic observations in aromatic L-amino acid decarboxylase 
deficiency." Neurology 53(6): 1205-1211 PMCID: 
Swoboda, K. J., J. P. Saul, C. E. McKenna, N. B. Speller and K. Hyland (2003). "Aromatic L-amino acid 
decarboxylase deficiency: overview of clinical features and outcomes." Ann Neurol 54 Suppl 6: 

AAV2-hAADC / Primary AADC Deficiency 
Bankiewicz / OSU 
Version 14.0 
Page 78 of 78 
August 3, 2020 
 
 
S49-55 PMCID: 
Szczypka, M. S., K. Kwok, M. D. Brot, B. T. Marck, A. M. Matsumoto, B. A. Donahue and R. D. 
Palmiter (2001). "Dopamine production in the caudate putamen restores feeding in dopamine- 
deficient mice." Neuron 30(3): 819-828 PMCID: 
Varni, J. W., M. Seid and P. S. Kurtin (2001). "PedsQL 4.0: reliability and validity of the Pediatric 
Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations." Med 
Care 39(8): 800-812 PMCID: 
Voges, J., R. Reszka, A. Gossmann, C. Dittmar, R. Richter, G. Garlip, L. Kracht, H. H. Coenen, V. 
Sturm, K. Wienhard, W. D. Heiss and A. H. Jacobs (2003). "Imaging-guided convection- 
enhanced delivery and gene therapy of glioblastoma." Ann Neurol 54(4): 479-487 PMCID: 
Weaver, F. M., K. Follett, M. Stern, K. Hur, C. Harris, W. J. Marks, Jr., J. Rothlind, O. Sagher, D. Reda, 
C. S. Moy, R. Pahwa, K. Burchiel, P. Hogarth, E. C. Lai, J. E. Duda, K. Holloway, A. Samii, S. 
Horn, J. Bronstein, G. Stoner, J. Heemskerk, G. D. Huang and C. S. P. S. Group (2009). "Bilateral 
deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a 
randomized controlled trial." JAMA 301(1): 63-73 PMCID: 2814800 
Ziegler, D. A., J. S. Wonderlick, P. Ashourian, L. A. Hansen, J. C. Young, A. J. Murphy, C. K. 
Koppuzha, J. H. Growdon and S. Corkin (2013). "Substantia nigra volume loss before basal 
forebrain degeneration in early Parkinson disease." JAMA Neurol 70(2): 241-247 PMCID: