Sulfamidase Brain Drug Delivery in Sanfilippo Syndrome

DESCRIPTION provided by applicant Type IIIA Mucopolysaccharidosis MPS also known as Sanfilippo A syndrome is a genetic disease that affects the lysosomal enzyme N sulfoglucosamine sulfohydrolase SGSH also called sulfamidase Consequently patients with MPS IIIA develop extensive lysosomal storage product accumulation in the brain Children born with MPS IIIA develop multiple brain disorders including mental retardation and hydrocephalus The current therapy for lysosomal storage disorders is Enzyme Replacement Therapy ERT with the recombinant human enzyme However ERT will not treat the brain of MPS IIIA because SGSH does not cross the blood brain barrier BBB The present work will continue work on the development of a new treatment of the brain of MPS IIIA which is a genetically engineered biopharmaceutical fusion protein named AGT The SGSH is genetically fused to a BBB molecular Trojan horse which is a genetically engineered peptidomimetic monoclonal antibody MAb against an endogenous BBB peptide receptor 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 Phase I studies show the HIRMAb SGSH fusion protein could be engineered and expressed by stably transfected host cells The fusion protein retained high affinity binding to the HIR and retained high SGSH enzyme activity The proposed phase II work will develop a manufacturing plan that can be replicated for future GMP manufacturing The AGT produced in phase II will be evaluated for safety toxicology and pharmacokinetics in a Rhesus monkey dose finding study The completion of this work will enable entry of the AGT drug development program into GLP toxicology and GMP manufacturing required for submission of an IND to begin treatment of the brain in patients with MPS IIIA PUBLIC HEALTH RELEVANCE Mucopolysacchridosis Type IIIA or Sanfilippo A Syndrome is an inherited condition where patients develop severe brain abnormalities owing to the genetic defect in the gene encoding the lysosomal enzyme N sulfoglucosamine sulfohydrolase SGSH Enzyme replacement therapy ERT is not effective for the brain because the SGSH does not cross the blood brain barrier BBB This research will develop a new treatment for the brain in patients with MPSIIIA which involves the re engineering of human SGSH as an IgG fusion protein that crosses the human BBB