Enzyme replacement therapy of the brain in Mucopolysaccharidosis Type II

DESCRIPTION (provided by applicant): Type II Mucopolysaccharidosis (MPS), also known as Hunter's syndrome, is a genetic disease that affects the lysosomal enzyme, iduronate-2-sulfatase (IDS). Consequently, patients with MPS-II develop extensive lysosomal storage product accumulation in tissues, including the brain. Children born with MPS-II develop multiple brain disorders including mental retardation and hydrocephalus. The current therapy for MPS-II is Enzyme Replacement Therapy (ERT) with the recombinanthuman enzyme, IDS. However, ERT does not treat the brain of MPS-II, because IDS 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-II, which is a genetically engineered biopharmaceutical fusion protein. The IDS 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 IDS is fused to the heavy chain of the HIRMAb to create a new chemical entity, called the HIRMAb-IDS fusion protein. Phase I studies show the HIRMAb-IDS 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 IDS enzyme activity. The proposed phase II work will develop a manufacturing plan that can be replicated for future GMP manufacturing. The AGT-182 produced in phase II will be evaluated for safety, toxicology and pharmacokinetics in 8 Rhesus monkeys. The completion of this work will enable entry of the AGT-182 drug development program into GLP toxicology and GMP manufacturing required for submission of an IND to begin treatment of the brain inpatients with MPS-II. PUBLIC HEALTH RELEVANCE: Mucopolysacchridosis Type II, or Hunter's Syndrome, patients develop severe brain abrormalities, owing to the genetic defect in the gene encoding the lysosomal enzyme, iduronate-2-sulphatase (IDS). Enzyme replacement therapy (ERT) is not effective for the brain, because the IDS does not cross the blood-brain barrier (BBB). This research will develop a new treatment for the brain in patients with Hunter's Syndrome, which involves the re-engineering of human IDS as a fusion protein that crosses the human BBB.