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-184. 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-184 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-184 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.
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.
|Boado, Ruben J; Lu, Jeff Zhiqiang; Hui, Eric Ka-Wai et al. (2014) Insulin receptor antibody-sulfamidase fusion protein penetrates the primate blood-brain barrier and reduces glycosoaminoglycans in Sanfilippo type A cells. Mol Pharm 11:2928-34|