Metachromatic Leukodystrophy Enzyme Drug Development

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DESCRIPTION (provided by applicant): Metachromatic leukodystrophy (MLD) is an genetic disease caused by mutations in the gene encoding the lysosomal enzyme, arylsulfatase A (ASA). Symptoms including neurodegeneration and mental retardation appear during infancy or childhood; and early death can occur due to organ damage in the brain. Enzyme replacement therapy (ERT) cannot treat the brain, since recombinant ASA does not cross the blood-brain barrier (BBB). Accordingly, clinical trials of children with MLD and recombinant ASA have been abandoned. The present work will re-engineer human ASA 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 ASA is fused to the heavy chain of the HIRMAb to create a new chemical entity, called the HIRMAb-ASA fusion protein. Feasibility studies with the HIRMAb-ASA fusion protein were enabled following the cloning of a high producing, stably transfected host cell line. The HIRMAb-ASA fusion protein retains high ASA enzyme activity and high binding to the HIR. This phase I SBIR work will further validate the pharmacologic activity of the HIRMAb-ASA fusion protein in MLD fibroblasts, using ASA enzyme activity assays and confocal microscopy. The HIRMAb-ASA fusion protein penetration of the BBB in vivo will be confirmed in the Rhesus monkey. This work provides the rationale for future phase II studies that provide the bridge to subsequent GMP/GLP work that supports an IND for treatment of MLD with the HIRMAb-ASA fusion protein. PUBLIC HEALTH RELEVANCE: Metachromatic leukodystrophy (MLD) is an genetic disease caused by mutations in the gene encoding the lysosomal enzyme, arylsulfatase A (ASA). Enzyme replacement therapy cannot treat the brain, since recombinant ASA does not cross the blood-brain barrier. The present work will re- engineer human ASA to enable transport across the BBB using a molecular Trojan horse technology.