Iduronidase Replacement Therapy of the Brain in Hurler's Syndrome

DESCRIPTION (provided by applicant): There are over 40 lysosomal storage disorders, and most of these diseases affect adversely the central nervous system (CNS). The mainstay of treatment is enzyme replacement therapy (ERT). However, ERT is not effective f or the brain, because the enzymes do not cross the brain capillary wall, which forms the blood-brain barrier (BBB) in vivo. Without treatment of the CNS, the young patients are destined to progressive neurodegeneration and death. The limiting factor in the future treatment of these diseases is the transport of the enzyme across the BBB. Bypass of the BBB with direct injection into the brain is not effective, because only a small part of the brain is treated with a trans-cranial delivery system. Conversely, virtually all cells of the brain can be treated with a trans-vascular delivery system that enables the enzyme to cross the BBB following intravenous administration. A new approach to the BBB delivery of large molecules such as enzymes is the molecular Troj an horse technology. A bi-functional fusion protein is produced with genetic engineering, wherein the missing recombinant enzyme is fused to a BBB molecular Trojan horse. The latter is a genetically engineered protein that is able to cross the human BBB by receptor- mediated transcytosis on endogenous BBB peptide transport systems. Pre-clinical studies show that a large enzyme with a molecular weight gt100,000 Daltons, can be delivered to brain via transport across the BBB, following attachment to a BBB rec eptor-specific Trojan horse. The present work will produce a novel fusion gene encoding human iduronidase and a genetically engineered molecular Trojan horse, which will allow the production of the corresponding fusion protein, AGT-181. This new fusion pro tein will be a new treatment of the brain in Hurler's syndrome. The fusion gene will be incorporated in a eukaryotic expression vector followed by permanent transfection of cells. These phase I studies will enable production of a permanently transfected ma mmalian host cell line for future manufacturing of AGT-181.