Mucopolysaccharidosis (MPS) Type IIIA, also called Sanfilippo A syndrome, is a genetic disease caused by mutations in the gene encoding the lysosomal enzyme, N-sulfoglucosamine sulfohydrolase (SGSH), also called sulfamidase. Symptoms including neurodegeneration and mental retardation appear during infancy or childhood;and early death occurs due to organ damage in the brain. Enzyme replacement therapy (ERT) cannot treat the brain, since recombinant SGSH does not cross the blood-brain barrier (BBB). Accordingly, clinical trials on the treatment of children with MPSIIIA with intravenous recombinant SGSH have been abandoned. The present work will re-engineer human SGSH to enable transport across the BBB using a molecular Trojan horse technology. A molecular Trojan horse is a genetically engineered peptidomimetic monoclonal antibody (MAb) against an endogenous BBB peptide receptor, such as the human insulin receptor (HIR). The human SGSH is fused to the heavy chain of the HIRMAb to create a new chemical entity, called the HIRMAb-SGSH fusion protein. Feasibility studies with the HIRMAb-SGSH fusion protein were enabled following the cloning of a high producing, stably transfected host cell line. The HIRMAb-SGSH fusion protein retains high SGSH enzyme activity and high binding to the HIR. This phase I SBIR work will further validate the pharmacologic activity of the HIRMAb-SGSH fusion protein in MPSIIIA fibroblasts, using SGSH enzyme activity assays and confocal microscopy. The HIRMAb-SGSH fusion protein penetration of the BBB in vivo will be confirmed in the Rhesus monkey. This work provides the rationale for future phase II studies that provide the bridge to subsequent GMP/GLP work that supports an IND for treatment of MPSIIIA with intravenous HIRMAb-SGSH fusion protein.

Public Health Relevance

Mucopolysaccharidosis (MPS) Type IIIA, also called Sanfilippo A syndrome, is a genetic disease caused by mutations in the gene encoding the lysosomal enzyme, N-sulfoglucosamine sulfohydrolase (SGSH), also called sulfamidase. Enzyme replacement therapy cannot treat the brain, since recombinant SGSH does not cross the blood-brain barrier. The present work will re- engineer human SGSH to enable transport across the BBB using a molecular Trojan horse technology.

Agency
National Institute of Health (NIH)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43NS088868-01
Application #
8771402
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Armagen Technologies, Inc.
Department
Type
DUNS #
City
Calabasas
State
CA
Country
United States
Zip Code
91302