PROJECT 3: MUCOPOLYSACCHARIDOSIS TYPE 1 (MPS1)

项目 3：粘多糖中毒 1 型 (MPS1)

• 批准号: 10668620
• 负责人: Beverly L. Davidson
• 金额: $ 106.93万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668620
• 关键词: 10 year old; 2 year old; Address; Adenine; Adult; Age Months; Biochemical; Biodistribution; Birth; Child; Clinical Trials; Congenital musculoskeletal anomalies; Dependovirus; Disease; Dose; Drug Kinetics; Enzymes; Exhibits; Fibroblasts; Funding; Genes; Genotype; Glycosaminoglycans; Goals; Guide RNA; Heart Diseases; Hematopoietic Stem Cell Transplantation; Hepatocyte; Hepatosplenomegaly; Hernia; Heterozygote; Human; Incidence; Infant; L-Iduronidase; Lead; Liver; Lysosomal Storage Diseases; Metabolic; Metabolic Diseases; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mus; Musculoskeletal Diseases; Mutation; Neurocognitive; Organ; Outcome; Pathology; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phenotype; Prior Therapy; Property; Retina; Route; Safety; Sheep; Therapeutic; Transplantation; United States Food and Drug Administration; autosome; base editing; base editor; causal variant; conditioning; cost; disease phenotype; enzyme replacement therapy; fetal; gallium arsenide; genome editing; immunogenic; improved; in utero; in vivo; ineffective therapies; meetings; mouse model; mutation correction; novel strategies; pharmacologic; postnatal; pre-Investigational New Drug meeting; preclinical study; prenatal; prevent; response; therapeutic genome editing

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.

项目概要 I 型粘多糖贮积症（MPSI，Hurler 综合征）是一种常染色体隐性遗传性溶酶体贮积病。 这种病理学在出生前就开始了，未经治疗的儿童在 10 岁时死于心肺并发症 年龄。既定的治疗方法对先前存在的病理无效，并且包括昂贵的、终生的、 免疫原性酶替代疗法和造血干细胞移植。 GàA突变 (W402X)，可通过腺嘌呤碱基编辑进行校正，占患者的 40%，具有很强的 基因型-表型相关性——所有纯合 W402X 患者均表现出严重疾病。项目3将重点 基于 AAV 的腺嘌呤碱基编辑 MPSI 产后治疗，旨在提交 IND 申请 并开始MPSI的临床试验和产前碱基编辑治疗，目的是进行临床前 五年资助期内的研究，如果产后临床试验能够最终申请 IND 证明是成功的。