Exhibit 10.8

Execution Copy

FOURTH ADDENDUM

TO THE RESEARCH AND LICENSE AGREEMENT

This Fourth Addendum to Research and license Agreement (the “Fourth Addendum”)
is made by and between the Technion Research and Development Foundation Ltd.
(“TRDF”) and Eloxx Pharmaceuticals Ltd. (“Licensee” or “Eloxx”).

Whereas, TRDF and Eloxx are parties to a Research and License Agreement with an
effective date of August 29th 2013 (the “License Agreement”), as amended on
November 26th, 2013 (“First Amendment”), January 14th, 2014 (“Second
Amendment”), June 9th, 2014 (“Third Amendment”), August 3rd 2014 (“First
Addendum”), January 21st, 2015 (“Second Addendum”) and February 9th 2015 (“Third
Addendum”) (collectively, the “Agreement”); and

Whereas, according to Section 1.26 to the License Agreement, the first Research
Period has ended on September 30th, 2014 (“First Research Period”) and the First
Research Plan was completed respectively (“First Research Plan”);and

Whereas, the parties desire to extend and continue the Research Period and the
Research for a second year; and

Whereas, the parties desire to continue the relationship contemplated by the
Agreement and therefore to further amend the Agreement as set forth herein;

NOW, THEREFORE, the parties hereby agree as follows:

 

1. Unless otherwise defined herein, capitalized terms used in this Fourth
Addendum shall have the meaning assigned thereto in the Agreement.

 

2. The parties wish to extend the Research Period for a second year, commencing
upon the expiration of the First Research Period, on October 1st, 2014 for
twelve (12) months until September 30th, 2015 (“Second Research Period”). The
extension shall be on the same terms and conditions as contained in the
Agreement unless otherwise agreed in this Fourth Addendum.

 

3. Exhibit D to the Agreement is hereby replaced with a new Exhibit D attached
hereto (“Second Research Plan”).

 

4. The parties wish to set the terms tor the funding for the performance of the
Second Research Plan during the Second Research Period, and replace section
2.2.1 of the License Agreement, as follows:

 

  a) Licensee shall fund the Research to be performed during the Second Research
Period under the Second Research Plan in the total amount of fifty thousand US
Dollars ($50,000) in accordance with the following schedule:

 

  1) First installment of twenty five thousand US Dollars ($25,000) shall be
paid upon signing this Fourth Addendum.

 

  2) Second installment of twenty five thousand US Dollars ($25,000) shall be
paid upon completion of the Second Research Plan and no later than October 1st
2015.

--------------------------------------------------------------------------------

Execution Copy

 

  b) V.A.T as applicable on time of payment shall be added to each installment.

 

  c) TRDF shall issue a proper invoice for each installment.

 

5. Except as amended herein, all other terms and conditions of the Agreement
shall remain in full force and effect.

 

ELOXX PHARMACEUTICALS LTD. DEVELOPMENT  

  THE TECHNION RESEARCH & FOUNDATION LTD.

By:  

/s/ Silvia Norman

    By:  

/s/ Mano Medalsi

  Name: Silvia Norman     Name: Mano Medalsi, CPA   Title: CEO     Title:  
Date: 24/4/15     Date: 29/4/15  

 

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Exhibit D

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Submitted to Eloxx Pharmaceuticals LTD

Research Plan

(Continuation for the second year 1.10.2014-30.092015)

Title

Development of Aminoglycose-Based Drug for Treatment of Human Genetic Diseases
and Many Forms of Cancer Caused by Nonsense Mutations

I.     Brief Summary of the First Year’s Research

The two specific aims were: To provide Eloxx with all the important lead
compounds developed by us in appropriate quantities (as agreed and signed) for
the validation of our previously published data, along with the detailed
protocols of the synthesis and biological evaluations performed in our labs (Aim
#1); Further modifications of the developed leads and/or development of new lead
structures for improved efficacy as potential drugs (Aim #2). The main
achievements include:

(1) We successfully synthesized all the lead compounds, provided them to Eloxx,
and the company has successfully validated with these compounds the entire
biological and toxicity data previously reported by us.

(2) We have generated a new series of N1-alkyl derivatives on the disaccharide
scaffold and demonstrated their improved activity in comparison to parent
compounds. Encouraged, the best disaccharide derivative NB146 was further
converted to the corresponding trisaccharide derivative, NB147. Both these new
leads (NB146 and NB147) were provided to Eloxx for further assessment their
biological tests.

(3) By developing a simple and robust synthetic scheme for the modification of
the developed leads as poly-ester derivatives, we have produced two such new
derivatives Bz-G418 (a prototype structure for the proof-of-concept) and
Bz-NB124 (along with their parent structures) and provided them to Eloxx for
further assessment their biological tests.

In addition, two workshops have organized by the PI during this grant period
with Eloxx together with a professional in CF, Prof S. Rowe (UAB, USA) and the
professional in Hurler syndrome, Prof. D. Bedwell (UAB, USA) to critically
discuss our recent developments and future progresses.

II.     Proposed Working Plan for the Second Year Research

Specific Aims

Aim # 1: Rational Design and Synthesis of New Readthrough Drugs. Our design
principles integrate the insights from the first year’s achievements in our lab
along with the insights in other labs in order to construct new classes of
compounds by a structure-based approach. Several sets of structurally distinct
chemical compounds will be included in the initial library and promising lead
compounds will be further refined for better cell permeability and prolonged
in-vivo action. The synthesis will use state-of-the-art strategies for the
assembly of complex carbohydrate, along with the convenient up-to-date
analytical techniques.

Aim #2: Chemical Modification of NBs for Improved Cell Permeability and Oral
Bioavailability. We will continue the project from the first year on the
polyester derivatives of NBs and this strategy will be further expanded with
polyamide derivatives and with the special modifications of NBs as pro-drugs for
better blood-brain-barrier (BBB) permeability.

Aim #1- (a) rational design of pseudo-disaccharide scaffolds: Based on our
previous results with development of lead structures of NB-series, we propose to
modify these compounds as well as to extend our study to more diverse structures
with potentially improved suppression activity and lower toxicity. We will probe
the pseudo-disaccharides of set1 (Fig. 1) as the minimum basic structures. The
rationale in selecting them is based on our observations with previous leads
exhibiting C6’-OH, and that further modifications by inserting either
unsaturation at ring I (glucosamine ring, compounds 1-9) or the 6’,7’-diol
(compounds 10-11) are expected to improve their specificity

 

LOGO [g542149g0315202852931.jpg]

 

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Timor Baasov

 

LOGO [g542149g0315202853072.jpg]

towards the cytoplasmic A-site, leading to enhanced readthrough and reduced
toxicity. This expectation is supported by: (i) the aminoglycoside (AG)
sisomicin that exhibits a similar unsaturated ring between C4’- C5’ at ring I
displays better antibacterial activity than similar 4,6-disubstituted AGs with a
saturated ring I, like gentamicin, tobramycin and amikacin. The superior
antibacterial activity of sisomicin has been attributed to its specific binding
mode1: while a typical saturated ring I with a chair conformation stacks on
G1491 through CH-p interactions, the unsaturated ring I of sisomicin stacks with
a partially planar conformation through p -p interactions with G1491 and
achieves a closer fit within the binding pocket; (ii) while sisomicin is active
only against bacteria, 6’-hydroxysisomicin possesses promising antiprotozoal
activity2: a comparison of stacking interactions between G1491 and ring I of
6’-hydroxysisomicin and geneticin in the protozoal A-site clearly favors the
former (Fig. 2A). 6’-hydroxysisomicin can adopt a lower energy conformation
within the protozoal A-site, leading to the entropically favorable burying of
the hydrophobic region of ring I with optimized p-p stacking on G1491. (iii) Our
recently solved crystal structure of G418 bound to a model of the Leishmania
ribosomal A-site supported the above notions3: the ring I of G418 is fixed into
the Leishmania A-site due to a stable pseudo pair with G1408 (Fig. 2B) and the
additional H-bonds O3’ LOGO [g542149j5.jpg] and LOGO [g542149j3.jpg] LOGO
[g542149j4.jpg] on the opposite site of the pseudo pair (Fig. 2C), leading to an
unfavorable stacking of ring I with the A1491. [Note that one of the major
differences between the protozoal and Leishmanial A-sites is the nucleotide at
position 1491 (E. coli numbering): G1491 in most protozoa and A1491 in
Leishmania; therefore the Leishmanial ribosome shares greatest similarity with
human ribosomes, with only a single nucleotide differentiating the AGs putative
binding sites (U1409 in Leishmania vs. C1409 in human]. Therefore, the deletion
of only C4’-OH (1-9, R1=OH, Fig 1) with simultaneous introduction of C4’-C5’
double bond, can make ring I relatively free to move within the binding pocket
and form stronger n-n stacking with A1491.

The rationale for the selective attachment of (S)-4-amino-2-hydroxybutanoyl
(AHB) at the N1 position of set1 (R=AHB) is based on the highly positive impact
of this group (for example in NB84) compared to their parent structures (for
example NB74), respectively4-8. Therefore, we will continue this approach in new
designs. Finally, in all set1 structures we preserved the C6’-OH function as a
crucial motif for favorable H-bond interactions between ring I of AG and G1408
(Fig. 2B). We anticipate that the deletion of C4’-OH or C3’,C4’-hydroxyls with a
simultaneous introduction of unsaturation on ring I will make the ring
relatively “free” to move within the binding pocket for better pseudo-pair
interaction with G1408 and improved p-p stacking with A1491 (Fig. 2C). The
recent comparative x-ray data of G418 and 6’-hydroxysisomicin in complex with
the bacterial and protozoal A-sites support this expectation1-2 (Fig. 2A). In
order to form a pseudo pair with 6’- hydroxysisomicin, the G1408 residue in the
protozoal A-site shifts toward the deep/major groove compared with the position
of A1408 in bacterial A-site, while ring I rotates approximately 13º around O4-
C1’ glycosidic bond between rings I and II; allowing the formation of a stable
pseudo-pair between the ring I of 6’- hydroxysisomicin and G1408, along with
the simultaneous strong p-p stacking of ring I with G1491.

 

LOGO [g542149g0315202853508.jpg]

 

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Timor Baasov

 

While these data support the likelihood that the compounds 1-9 of set1
structures (Fig. 1) with 6’-OH and unsaturation at ring I may perform better
than previous leads with the saturated ring I, we want to introduce additional
structural motifs at the C6’- region that would further increase this
expectation. We plan to replace the CH2OH (and/or CH(CH3)OH) at 6’-position with
the vicinal 6’,7’-diol (compounds 10-11, Fig.1). The replacement of C6’-OH with
6’,7’-diol is expected to generate stronger H-bond interactions of ring I with A
site residues G1408 and C1409 resulting in better pseudo-disaccharide scaffold
of set1 (Fig. 3). Following important points in Fig. 3 are of note. First,
unlike our solved structure of G418 bound to Leishmania A-site (Fig. 2B and 2C)
in which ring I of G418 makes two H-bonds with G1408, the structure of G418
bound to the entire yeast ribosome recently reported by Yusupov and co-workers9,
shows only one H-bond between O6’ and G1408 nitrogen (Fig. 3). Modelling ring I
of the 6’,7’-diol 10 onto this structure of Yusopov, clearly shows that O7’-OH
can make additional H-bond with the oxygen of C1409.

To test this issue, we initially synthesized compound 10 (Fig. 1) as a single
diastereomer at C6’ with unknown configuration (the complete assignment of the
absolute configuration of 10 at C6’, along with the synthesis of its C6’-
distereomer are underway). Preliminary in-vitro suppression tests demonstrated
that 10 exhibits superior readthrough to that of 12, and paromamine (Fig. 4).
Interestingly, installation of 6’,7’-diol on the paromamine scaffold
(10) dramatically increases its in-vitro readthrough activ ity. It is of note
that the observed activity increase in 10 is far higher than the impact of the
chiral (R)-6’- methyl group in 12, which was to date our most favorable
pharmacophore at C6’- regon7,8. With compound 10 we are already one step ahead!
Further installation of chiral (R)-6’-methyl group and/or N1-AHB group on
compound 10 will likely provide additional improvement of this performance, and
these potentials will be tested in the subsequent steps.

 

LOGO [g542149g0315202853898.jpg]

In addition to 10 we also synthesized the simplest representative of set1
structures, compound 1 (R=R1=R2=H, Figs. 1 and 2). Preliminary comparative
in-vitro suppression tests demonstrated that 1 exhibits superior readthrough to
that of its parent paromamine and is very similar to that of compound 12 (Fig.
4). These data suggest that the anticipated p-p stacking interaction of the
unsaturated ring I of 1 with A1491 is much stronger than the CH-p interactions
of the saturated ring I of paromamine with A1491. The data in Fig. 4 also
suggests that the advantage of such stacking interactions in 1 (paromamineg1) is
similar to that of (R)-6’-methyl group in 12 (paromamineg12), and thus
identifies unsaturation at ring I as a potential new pharmacophore.

Aim #1- b) rational design of pseudo-trisaccharide scaffolds: It should be noted
that the set1 structures (Fig. 1) are not expected to possess significant PTC
suppression activity (Fig. 4); rather they will be used as scaffolds for the
construction of new efficacious structures by attaching various sugar and/or
acyclic appendages. For a systematic study, the same modifications will be
performed on all pairs of set1, with the aim to reach the best lead compound. As
a ring III we have developed a new structure of (S)-
5’’-amino-5’’-methyl-D-ribose, and its advantage over 5”-aminoribose was evident
in our previous leads7,8. Therefore, we will use this novel ring III for the
generation of new pseudo-trisaccharides (set2-set3, Fig. 5). Encouraged by the
preliminary data obtained with 10 (Fig. 4), we will scrutinize the
stereochemistry at C6’ of 10 and will assemble the corresponding pseudo-

 

LOGO [g542149g0315202854148.jpg]

 

6

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Timor Baasov

 

trisaccharides 13 and 14 (set2, Fig. 5), along with all the variations of
pseudo-trisaccharides with unsuterated ring I (compounds 15-22, set3, Fig. 5).
In addition, based on the observed strong impact of the vicinal 6’,7’-diol in 10
(Fig. 4), this variable (6’,7’-diol) will further be added to the planned
pseudo-trisaccharides of set3 structures in Fig. 5, to yield additional sets of
compounds incorporating the vicinal 6’,7’-diol and unsaturation at ring I.

Aim #2. a) Modification of lead structures for improved cell permeability and
oral bioavailability: Because AGs are highly charged, water soluble compounds,
they have poor intestinal absorption and are usually injected. In addition, AGs
are short-lived in the circulatory system, rapidly eliminated by glomerular
filtration in the kidney. They also exhibit poor permeability into eukaryotic
cells, which requires higher dosages that often cause harmful side effects that
limit their use in therapy. In order to overcome these limitations we designed
different sets of compounds. One of such sets (Fig. 6) considers that all
hydroxyls of the AG are replaced by esters. The rationale is to increase the
lipophilicity and cell-permeability of the drugs, improve in-vivo half-life and
oral bioavailability. These changes should provide important therapeutic benefit
over treatment with the initial lead alone.

The suggested modifications on NB124 and G418 (Fig. 6) to yield the
corresponding per-benzoate esters (OBz, 51 and 52, respectively) are based on
the following observations. (i) In our most recent comparative study of our lead
compounds using an extended repertoire of CF cell lines, reporters, assays and
animal models, comp. NB124 was able to most effectively rescue CFTR function,
was superior to gentamicin, exhibited favorable pharmacokinetics, and was less
cytotoxic than gentamicin in the explant model of ototoxicity10; (ii) the
benzoate esters 51 and 52 are chemically more stable than the corresponding
simple alkyl asters (like acetate, isobutirate, isopropionate); (iii) the
poly-esters 51 and 52 can easily be prepared in good overall yields from the
corresponding AGs in three steps (Boc2O, Et3N, H2O/MeOH; BzCl, Py, 4DMAP; TRA,
CH2Cl2); (iv) to test our hypothesis we initially used 52 as a prototype derived
from commercial G418.

 

LOGO [g542149dsp81aa.jpg]

Preliminary tests of 52 against its parent G418 demonstrated that 52 lacks any
readthrough activity both in cell free (see the data in the 1st year research
report) assays and HEK293 cells stably expressing UGAC/CGAC dual luciferase
(Fig. 7A) even when the incubation time was extended up to 72 hrs.
Interestingly, when we tested the antibacterial activities of G418 and 52, we
found that while the activity of 52 was similar to that of G418 against various
G- and G+ WT bacteria, the MIC values of 52 were significantly lower than that
of G418 in bacterial strains harboring plasmids of AG resistance determinant
enzymes (see the data in the 1st year research report). Encouraged, we argued
that HEK293 cells, being engineered cell lines, might not contain the required
esterases to hydrolyze the benzoate esters in 52. Indeed, using MEFs derived
from homozygous Idua-W402X mice11, we found that the activity of 52
significantly exceeds that of G418 at all incubation times and concentrations
tested. At a dose of only 13.6 micromolar, treated cells had already reached the
glycosaminoglycan (GAG) levels found in WT cells (Fig. 7B). These encouraging
data with 52 prompted us to prepare compound 51 (see the data in the 1st year
research report), which is currently under similar tests in Idua-W402X MEFs (by
our collaborator D. Bedwell at Univ. of Alabama, Birmingham) and CF cell lines
(primary human bronchial epithelial, HBE cells, G542X/delF508, S. Rowe at the
UAB). In-vivo tests in the Idua-W402X mice (D. Bedwell) will follow these
experiments.

 

LOGO [g542149dsp81b.jpg]

 

7

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Timor Baasov

 

LOGO [g542149dsp82.jpg]

Aim #2 b) Modifications for improved capacity to pass the blood-brain barrier
(BBB). While we have been successful in identifying promising nonsense
suppression agents (NB84) for the Idua-W402X mutation and partially alleviating
the primary GAG storage defect associated with MPS I-H within a variety of
tissues (including brain), we have been unable to completely restore GAG levels
in the mouse model, even in a long-term, 28-week drug-treatment12,13. Even
though the newly proposed sets of compounds might prove better than the
previously examined leads (especially the structures with elevated lipophilicity
like 51) for treatment of MPS I-H, we propose to also test a brain-targeted
chemical delivery system (CDS)14 which is expected to produce a more robust
therapeutic response. The approach is based on the attachment of a
dihydropyridine moiety as a carrier for delivering drugs through the BBB (Fig.
8). This site-selective delivery will reduce the exposure of the body to high
drug levels and consequently increase their therapeutic index. Since NB84 has
already been proven to significantly moderate disease progression in-vivo in our
MPS I-H mouse model ,12 we will now synthesize the new derivative of NB84, the
compound NB84-CDS (Fig. 11). We (our collaborator at UAB, D. Bedwell) will then
determine whether delivery of NB84-CDS through the BBB is better than NB84 in a
long term study using established biochemical and immunohistochemical assays as
previously described12.

REFERENCES

 

(1) Kondo, J., Koganei, M., and Kasahara, T. (2012) Crystal Structure and
Specific Binding Mode of Sisomicin to the Bacterial Ribosomal Decoding Site. ACS
Med. Chem. Lett. 3,9, 741-744.

(2) Kondo, J., Koganei, M., Maianti, J. P., Ly, V. L., and Hanessian, S.
(2013) Crystal Structures of a Bioactive 6’-Hydroxy Variant of Sisomicin Bound
to the Bacterial and Protozoal Ribosomal Decoding Sites. ChemMedChem 8, 733–739.

(3) Shalev, M., Kondo, J., Kopelyanskiy, D., Jaffe, C. L., Adir, N., and Baasov,
T. (2013) Identification of the molecular attributes required for aminoglycoside
activity against Leishmania. Proc. Natl. Acad. Sci. U. S. A. 110, 13333–13338.

(4) Nudelman, I., Rebibo-Sabbah, A., Cherniavsky, M., Belakhov, V., Hainrichson,
M., Chen, F., Schacht, J., Pilch, D. S., Ben-Yosef, T., and Baasov, T.
(2009) Development of novel aminoglycoside (NB54) with reduced toxicity and
enhanced suppression of disease-causing premature stop mutations. J. Med. Chem.
52, 2836–2845.

 

8

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Timor Baasov

 

(5) Nudelman, I., Glikin, D., Smolkin, B., Hainrichson, M., Belakhov, V., and
Baasov, T. (2010) Repairing faulty genes by aminoglycosides: development of new
derivatives of geneticin (G418) with enhanced suppression of diseases-causing
nonsense mutations. Bioorg. Med. Chem. 18, 3735–3746.

(6) Rebibo-Sabbah, A., Nudelman, I., Ahmed, Z. M., Baasov, T., and Ben-Yosef, T.
(2007) In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense
mutations underlying type 1 Usher syndrome. Hum. Genet. 122, 373–381.

(7) Kandasamy Atia-Glikin, D., Belakhov, V. and Baasov, T., J. (2011) Repairing
faulty genes by aminoglycosides: Identification of new pharmacophore with
enhanced suppression of diseases-causing nonsense mutations. Med Chem Comm 2,
165–171.

(8) Kandasamy, J., Atia-Glikin, D., Shulman, E., Shapira, K., Shavit, M.,
Belakhov, V., and Baasov, T. (2012) Increased selectivity toward cytoplasmic
versus mitochondrial ribosome confers improved efficiency of synthetic
aminoglycosides in fixing damaged genes: A strategy for treatment of genetic
diseases caused by nonsense mutations. J. Med. Chem. 55, 10630– 10643.

(9) De Loubresse, N. G., Prokhorova, I., Holtkamp, W., Rodnina, M. V., Yusupova,
G., and Yusupov, M. (2014) Structural basis for the inhibition of the eukaryotic
ribosome. Nature 513, 517-522.

(10) Gunn, G., Dai, Y., Du, M., Belakhov, V., Kandasamy, J., Schoeb, T. R.,
Baasov, T., Bedwell, D. M., and Keeling, K. M. (2014) Long-term nonsense
suppression therapy moderates MPS I-H disease progression. Mol. Genet. Metab.
111, 374-381.

(11) Keeling, K. M., Wang, D., Dai, Y., Murugesan, S., Chenna, B., Clark, J.,
Belakhov, V., Kandasamy, J., Velu, S. E., Baasov, T., and Bedwell, D. M.
(2013) Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense
Suppression. PLoS One 8, 4, e60478.

(12) Gunn, G., Dai, Y., Du, M., Belakhov, V., Kandasamy, J., Schoeb, T. R.,
Baasov, T., Bedwell, D. M., and Keeling, K. M. (2014) Long-term nonsense
suppression therapy moderates MPS I-H disease progression. Mol. Genet. Metab.
111, 374-381.

(13) Keeling, K. M., Wang, D., Dai, Y., Murugesan, S., Chenna, B., Clark, J.,
Belakhov, V., Kandasamy, J., Velu, S. E., Baasov, T., and Bedwell, D. M.
(2013) Attenuation of Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense
Suppression. PLoS One 8, 4, e60478.

(14) Bodor, N., and Buchwald, P. (2008) Retrometabolic drug design: Principles
and recent developments. Pure Appl. Chem. 80, 1669-1682.

III. Proposed Budget (in US Dollars) and Time Frame

 

      The proposed task    Time Frame    Budget
Requested      Remarks    Notes

Aim # 1

   Establishment of config. In 10 and synthesis of 13.   

6-12 months

   $ 15,000      One postdoc/student dedicated.   

PI T. Baasov

   Synthesis of 15 and preliminary biochem. Analysis of 10,13 and 15.   

6-12 months

   $ 15,000      One postdoc/student dedicated.          Total Aim #1:    $
30,000              

 

  

 

 

       

Aim # 2a

   Synthesis of NB84-esters and NB124-esters   

8-12 months

   $ 10,000      One postdoc/student dedicated.   

Aim # 2b

   Synthesis of NB84-CDS and its Preliminary biochemical analysis   

6-12 months

   $ 10,000      One postdoc/student dedicated.          Total Aim #2:    $
20,000              

 

  

 

 

              Grand total for the Aims # 1&2:    $ 50,000              

 

  

 

 

       

 

9

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Timor Baasov

 

NOTE the budget does not include ex vivo (MEFs) and in vivo studies required for
the project completion and only can be done with additional funding of
collaborators labs (Bedwell and Rowe at UAB)!

IV. Detailed Budget (in US Dollars)

Personnel:

 

Role in project         % Time      Salary  

1.

  

Lab. Assistant

  

Lab. Assistant

     50        12,000  

2.

  

Postdoctorant

  

Researcher

     50        12,000              

 

 

    

Total:

           24,000  

Supplies:

 

1. Chemicals, absolute & deuterated solvents

     18,000  

2. Lab. equipment, glassware, plastic ware

     2,000  

3. Biochemicals

     2,000  

4. In vitro and ex vivo assay kits

     2,000  

5. Chromatography material for various purifications

     1,000  

6. NMR and Mass Spectrometry tests

     1,000     

 

 

 

Total:

     26,000     

 

 

 

Grand Total:

   $ 50,000  

Budget Justification:

The requests for laboratory assistant and postdoctorant for the duration of the
grant period are in recognition of the amount of work required in this project.
Considerable effort will be expended in the syntheses of various lead compounds
discussed in the proposal, their structure determination and analysis, assays
for their activity. The request for materials, supplies, and
chemicals/biochemicals is an important part for a successful development and
completion of the project.

V. Investigators’ Curriculum Vitae

 

Surname:   

Baasov

      First name:   

Timor

Birthdate:   

January 3, 1954

        

(a) Education Background

 

From-To

  

Institution

  

Area of specialization

   Degree

1981-1986

   Weizmann Institute of Science    Chemistry    Ph. D.

1977-1979

   Tel-Aviv University    Chemistry    M. Sc.

1975-1977

   Tel-Aviv University    Chemistry    B. Sc.

Major research interest: Carbohydrate chemistry, Bioorganic and medicinal
chemistry, Drug design and development, Rational design of substrate and
inhibitors, Mechanistic enzymology.

(b) Employment

 

From-To

  

Institution

  

Research area

   Title

2004-

   Technion    Bioorganic Chemistry    Professor

3/1998-8/1998

   The Scripps Research Institute, Cal    Bioorganic Chemistry    Visiting Prof.

 

10

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Timor Baasov

 

1998-2003

   Technion    Bioorganic Chemistry    Assoc. Prof.

1990-1998

   Technion    Bioorganic Chemistry    Senior Lecturer

1988-1990

   Technion    Bioorganic Chemistry    Lecturer

1986-1988

   Harvard University    Bioorganic Chemistry    Post-Doct. Res.

VI. T. Baasov - List of Publications last three years (2011-2014)

 

1. C. Brendel, V. Belakhov, H. Werner, E. Wegener, J. Gaertner, I. Nudelman, T.
Baasov, P. Huppke. Readthrough of Nonsense Mutations in Rett Syndrome:
Evaluation of novel aminoglycosides and generation of a new mouse model. Journal
Molecular Medicine, 89, 389-398, (2011).

 

2. J. Kandasamy, D. Atia-Glikin, V. Belakhov, T. Baasov. Repairing faulty genes
by aminoglycosides: Identification of new pharmacophore with enhanced
suppression of diseases-causing nonsense mutations. Medicinal Chemistry
Communications, 2, 165-171 (2011).

 

3. S.M. Rowe, L.P. Tang, P. Sloane, K.Backer, M. Mazur, J. Buck;ey-Lauriel, I.
Nudelman, V. Belakhov, Z. Belok, E. Schwiebert, T. Baasov, D.M. Bedwell.
Suppression of CFTR Premature Termination Codons and Rescue of CFTR Protein and
Function by the Synthetic Aminoglycoside NB54. Journal Molecular Medicine
(Berl), 89, 1149-1154 (2011).

 

4. M. Vecsler, B. Ben Zeev, I. Nudelman, Y. Anikster, A. J. Simon, N. Amariglio,
G. Rechavi, T. Baasov, E. Gak. Ex Vivo Treatment with a Novel Synthetic
Aminoglycoside NB54 in Primary Fibroblasts from Rett Syndrome Patients
Suppresses MECP2 Nonsense Mutations. PLoS ONE, 6 (6), e20733 (2011).

 

5. H-L. R. Lee, C-C. Chen, T. Baasov, Y. Ron, J. P. Dougherty.
Post-transcriptionally Regulated Expression System in Human Xenogeneic
Transplantation Models. Molecular Therapy, 19(9), 1645-1655 (2011).

 

6. D. Wang , V. Belakhov, J. Kandasamy, T. Baasov, S-C. Li, Y-T Li, D.M.
Bedwell, K.M. Keeling. The designer aminoglycoside NB84 significantly reduces
glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse.
Molecular Genetics and Metabolism 105, 116-125 (2012).

 

7. T. Goldmann, N. Overlack, F. Möller, V. Belakhov, M. van Wyk, T. Baasov, U.
Wolfrum, and K. Nagel-Wolfrum. A comparative evaluation of NB30, NB54 and PTC124
in translational read-through efficacy for treatment of an USH1C nonsense
mutation. EMBO Molecular Medicine, 4, 1-14, (2012).

 

8. J. Kandasamy, D. Atia-Glikin, E. Shulman, K. Shapira, M. Shavit, V. Belakhov
T. Baasov. Increased Selectivity toward Cytoplasmic versus Mitochondrial
Ribosome Confers Improved Efficiency of Synthetic Aminoglycosides in Fixing
Damaged Genes: A Strategy for Treatment of Genetic Diseases Caused by Nonsense
Mutations. J. Med. Chem. 55(23), 10630-10643 (2012).

 

9. M. Schalev, J. Kandasamy, N. Skalka, V. Belakhov, R. Rosin-Arbesfeld, T.
Baasov. Development of generic immunoassay for the detection of a series of
aminoglycosides with 6’-OH group for the treatment of genetic diseases in
biological samples. Journal of pharmaceutical and biomedical analysis. 75, 33-40
(2013).

 

10. K.M. Keeling, D. Wang, Y. Dai, S. Murugesan, B. Chenna, J. Clark; V.
Belakhov, J. Kandasamy, S.E. Velu, T. Baasov, D.M. Bedwell. Attenuation of
Nonsense-Mediated mRNA Decay Enhances In Vivo Nonsense Suppression. PLoS ONE 8
(4), e60478 (2013).

 

11. M. Schalev, J. Kondo, D. Kopelyanskiy, C.L. Jaffe, N. Adir, T. Baasov.
Identification of the molecular attributes required for Aminoglycoside activity
against Leishmania. PNAS 110 (33), 13333-13338 (2013).

 

12. M. Kamei, K. Kasperski, M. Fuller, E. Parkinson-Lawrence, L. Karageorgos,,
V. Belakhov, T. Baasov, J.J. Hopwood, D.J. Brooks. Am inoglycoside-Induced
Premature Stop Codon Read-Through of Mucopolysaccharidosis Type I Patients Q70X
and W402X Mutations in Cultured Cells. Journal of Inherited Metabolic Disease
Reports. 13, 139-147 (2014)

 

13. X. Xue, V. Mutyam, L.P. Tang, S. Biswas, M. Du, L. A. Jackson, Y. Dai, V.
Belakhov, M. Shalev, F. Chen, J. Schacht, R. Bridges, T. Baasov, J. Hong, D. M.
Bedwell, S.M. Rowe. Synthetic Aminoglycosides Efficiently Suppress CFTR Nonsense
Mutations and Are Enhanced by Ivacaftor. Am. J. Respir. Cell Mol. Biol. 50 (4),
805- 816 (2014).

 

14. E. Shulman, V. Belakhov, G. Wei, A. Kendall, E. G. Meyron-Holtz, D.
Ben-Shachar, J. Schacht, T. Baasov. Designer aminoglycosides that selectively
inhibit cytoplasmic rather than mitochondrial ribosomes show decreased
ototoxicity: a strategy for the treatment of genetic diseases. J. Biol. Chem.
289(4), 2318-2330 (2014).

 

15. G. Gunn, Y. Dai, M. Du, V. Belakhov, J. Kandasamy, T.R. Schoeb, T. Baasov,
D.M. Bedwell, K.M. Keeling. Long-term nonsense suppression therapy with NB84
moderates MPS IH disease progression. Molec. Genet. Metabol. 111, 374-381
(2014).

 

11

--------------------------------------------------------------------------------

Timor Baasov

 

16. M. Shalev, T. Baasov. When Proteins Start to Make Sense: Fine-tuning of
Aminoglycosides for PTC Suppression Therapy. Med. Chem. Commun. 5, 1092-1105
(2014). Invited Review Perspective Article

Chapters in Books and other Publications

 

1. V. Mutyam, X. Xue, X. Jackson, L. Hong, S. Biswas, D. Bridges, T. Baasov, V.
Belakhov, D. Bedwell, S. Rowe. Use of transepithelial conductance as a screening
technique for identification of drugs that promote readthrough of premature stop
codons. Pediatric Pulmonology 48, page 232 (supplement 36; meeting abstract).
ISSN: 8755-6863 (2013).

 

2. K. Nagel-Wolfrum, T. Baasov, U. Wolfrum. Therapy strategies for Usher
syndrome Type 1C in the retina. Advances in experimental medicine and biology.
Vol. 801, pp. 741-747 (2014).

 

3. T. Baasov, M. Fridman. Foreword-The 17th European Carbohydrate
Symposium-EuroCarb17. Carbohydrate Research 389, 1 (2014). (Guest Editor of the
special issue.)

 

4. S. Garneau-Tsodikova, T. Baasov. Editorial – Carbohydrates Themed Issue. Med.
Chem. Commun., 5, 1010-1013 (2014). (Guest Editor of the special issue.)

 

12