PROJECT 2: HEREDITARY TYROSINEMIA TYPE 1 (HT1)

项目 2：遗传性酪氨酸血症 1 型 (HT1)

• 批准号: 10668619
• 负责人: William H. Peranteau
• 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/10668619
• 关键词: Adenine; Adherence; Biodistribution; Birth; Cause of Death; Cell Line; Clinical Trials; Coagulation Process; Cytosine; Dioxygenases; Disease; Disease model; Dose; Drug Kinetics; Early treatment; Enzymes; Fumarylacetoacetase; Funding; Genes; Germ-Line Mutation; Goals; Guide RNA; Hepatocyte; Herbicides; Human; Impairment; Lead; Life; Liver; Liver Failure; Liver diseases; Medical; Messenger RNA; Metabolic; Metabolic Diseases; Mus; Mutation; Neonatal; Neurologic; Nonsense Mutation; Outcome; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phenotype; Phenylalanine; Primary carcinoma of the liver cells; Prior Therapy; Proteins; Proximal Kidney Tubules; RNA Splicing; Risk; Safety; Sheep; Site; Therapeutic; Tyrosine; Tyrosinemias; United States Food and Drug Administration; autosome; base editing; base editor; dietary; dietary restriction; fetal; genome editing; high risk; in utero; in vivo; lipid nanoparticle; liver transplantation; meetings; nanoparticle delivery; neonatal period; non-compliance; novel strategies; pharmacologic; postnatal; pre-Investigational New Drug meeting; preclinical study; prenatal; renal tubular dysfunction; response; somatic cell gene editing; standard of care; succinylacetone; therapeutic genome editing

PROJECT SUMMARY Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive metabolic liver disease that can cause death in the first months of life and incurs an increased risk of hepatocellular cancer. The current treatment option—strict adherence to twice daily dosing with NTBC, a repurposed herbicide that inhibits HPD—is limited by high noncompliance rates. Liver transplant remains the only option for those patients that fail medical management. Genome editing to inactivate the HPD gene in the tyrosine catabolic pathway provides a potential universal, one- time, lifelong treatment for HT1 patients. Project 2 will focus on an LNP-based adenine base editing postnatal treatment of HT1, with the aim to file an IND application and begin a clinical trial, and prenatal base editing treatment of HT1, 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.

项目摘要 遗传性酪氨酸血症1型（HT 1）是一种常染色体隐性代谢性肝病，可导致死亡， 在生命的最初几个月，并增加患肝细胞癌的风险。目前的治疗方案-严格 坚持每天两次服用NTBC，一种抑制HPD的再用途除草剂， 不遵守率。肝移植仍然是那些医疗管理失败的患者的唯一选择。 在酪氨酸分解代谢途径中对HPD基因进行基因组编辑，提供了一种潜在的通用、单一的方法， 对HT 1患者进行终身治疗。项目2将重点关注基于LNP的腺嘌呤碱基编辑产后 HT 1的治疗，旨在提交IND申请并开始临床试验，以及产前碱基编辑 治疗HT 1，目的是在五年资助期内进行临床前研究， 如果产后临床试验证明成功，最终IND申请。