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Development and validation of therapy for mucopolysaccharidosis III

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 5U44NS089061-05
Agency Tracking Number: R44NS089061
Amount: $5,612,276.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: 103
Solicitation Number: PAR17-480
Solicitation Year: 2017
Award Year: 2018
Award Start Date (Proposal Award Date): 2018-09-30
Award End Date (Contract End Date): 2022-12-31
Small Business Information
200 16TH ST, APT 3D
Brooklyn, NY 11215-8441
United States
DUNS: 078416746
HUBZone Owned: No
Woman Owned: Yes
Socially and Economically Disadvantaged: No
Principal Investigator
 (347) 831-0246
Business Contact
Phone: (347) 831-0246
Research Institution

Project Summary
Sanfilippo disease (mucopolysaccharidosis type III; MPS III) is a devastating neurodegenerative lysosomal
storage disorder of childhood whose pathologic features are neurologic: slowing of development, severe
behavioral problems, progressive cognitive decline, dementia, and decline in motor skills leading to immobility,
unresponsiveness, and death. We have focused on MPS IIID caused by a deficiency of alpha-N-
acetylglucosamine-6-sulfatase (GNS). Because MPS IIID is rare (1 in a million) and affects the brain (which is
difficult to treat) no cure or treatment is available and there are at least three patients in the USA to our
knowledge. Dr. Patricia Dickson and Dr. Tsui-Fen Chou (LABioMed) have developed an enzyme replacement
treatment (ERT) for MPS IIID. Our strategy proposes to deliver recombinant human alpha-N-acetylglucosamine-
6-sulfatase (rhGNS) intrathecally or intraventricularly to effectively treat the underlying causes of the neurologic
symptoms that dominate MPS III pathology. ERTs are not a cure but can have a dramatic effect on the quality
of life and patient development. There are several examples of successfully commercialized ERT's (e.g.
laronidase (MPS I), idursulfase (MPS II), etc) and Biomarin recently received approval for an ERT for a form of
Batten disease, CLN2. Other ERTs for MPS I, II, and IIIB are in Phase I trials. Both the FDA and investors are
familiar with ERT and its commercialization path, which will greatly increase the chances of reaching a clinical
trial. We have produced rhGNS ~200 µg per 750 mL media in CHO cells, purified it to a specific activity of
~100,000 activity units/mg, demonstrated maximal enzymatic activity at pH 5.6, which is closer to lysosomal pH
(with low activity at neutral pH), demonstrated good enzymatic activity at 37ºC and showed it is stable for over
one month at 4 ˚C in artificial cerebrospinal fluid storage buffer. We demonstrated intracellular uptake of rhGNS
in MPS IIID fibroblasts when rhGNS is added to the media and confirmed that radiolabelled HS diminished 33-
65% in MPS IIID fibroblasts treated with rhGNS (to wild-type levels). We have since scaled up our production of
rhGNS so that we can study enzyme activity, lysosomal storage reduction, neuropathology and half-life
estimation in the recently characterized MPS IIID knock out mouse. After dosing knockout mice with a single
dose of ~5.3 ug rhGNS we have observed return of GNS activity to 50% wild-type levels in mouse brain
and a statistically significant reduction of markers of lysosomal storage in this model (NAGLU and
hexosaminidase acitivity) after 1 day of treatment. Our currently ongoing studies include histology and half-
life estimates after repeat dosing in knock out MPS IIID mice. LABioMed has filed a US patent on rhGNS
(pending) and Phoenix Nest, Inc. has licensed it. The pre-IND studies we now propose through this program
would include transferring production to a GMP facility, optimizing process for scale-up, and characterizing
product (aggregation, glycosylation, purity, activity, contamination, etc). We would also perform 2-animal model
pharmacotoxicity studies. Additionally, we would also need to perform other activities to satisfy regulatory agency
(FDA) requirements such as assay optimization and regulatory strategy. In order to treat 5 U.S. patients with a
possible dose of 90 mg every month (based on Sanfilippo A intrathecal sulfamidase doses), we will need to
produce 5,400 mg of rhGNS per year to meet U.S. clinical needs.

* Information listed above is at the time of submission. *

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