PROJECT 2: HEREDITARY TYROSINEMIA TYPE 1 (HT1)

项目 2：遗传性酪氨酸血症 1 型 (HT1)

基本信息

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
项目类别：
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

项目摘要

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.

项目概要遗传性酪氨酸血症 1 型 (HT1) 是一种常染色体隐性遗传代谢性肝病，可导致死亡生命的最初几个月会增加患肝细胞癌的风险。目前的治疗选择是严格的。坚持每天两次使用 NTBC（一种抑制 HPD 的新用途除草剂）受到高浓度的限制肝移植仍然是那些医疗管理失败的患者的唯一选择。基因组编辑使酪氨酸分解代谢途径中的 HPD 基因失活，提供了一种潜在的通用的、单- 项目 2 将重点关注基于 LNP 的产后腺嘌呤碱基编辑。 HT1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 HT1 的治疗，目的是在五年资助期内进行临床前研究，以实现如果产后临床试验成功，则最终申请 IND。