Sulfamidase Brain Drug Delivery in Sanfilippo Syndrome

DESCRIPTION (provided by applicant): 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 th