PROJECT 3: MUCOPOLYSACCHARIDOSIS TYPE 1 (MPS1)

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PROJECT SUMMARY Mucopolysaccharidosis type I (MPSI, Hurler syndrome) is an autosomal recessive lysosomal storage disease in which pathology begins before birth and untreated children die of cardiorespiratory complications by 10 years of age. Established treatments are ineffective against preexisting pathology and include costly, lifelong, immunogenic enzyme replacement therapy and hematopoietic stem cell transplantation. A GàA mutation (W402X), amenable to correction via adenine base editing, accounts for 40% of patients and has a strong genotype-phenotype correlation—all homozygous W402X patients exhibit severe disease. Project 3 will focus on an AAV-based adenine base editing postnatal treatment of MPSI, with the aim to file an IND application and begin a clinical trial, and prenatal base editing treatment of MPSI, with the aim of performing preclinical studies during the five-year funding period to enable an eventual IND application if the postnatal clinical trial proves successful.