PROJECT 3: MUCOPOLYSACCHARIDOSIS TYPE 1 (MPS1)

项目摘要 I型粘多糖贮积症（MPSI，Hurler综合征）是一种常染色体隐性溶酶体贮积病， 这种病理学在出生前就开始了，未经治疗的儿童在出生后10年内死于心肺并发症。 年龄现有的治疗方法对预先存在的病理无效，包括昂贵的，终身的， 免疫原性酶替代疗法和造血干细胞移植。A GàA突变 （W 402 X），可通过腺嘌呤碱基编辑进行校正，占患者的40%，并且具有强的免疫抑制作用。 基因型-表型相关性-所有纯合子W 402 X患者表现出严重的疾病。项目3将重点 基于AAV的腺嘌呤碱基编辑MPSI的产后治疗，目的是提交IND申请 并开始临床试验和MPSI的产前碱基编辑治疗，目的是进行临床前 在五年资助期内进行研究，以便在产后临床试验 证明是成功的

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.