项目 2：遗传性酪氨酸血症 1 型 (HT1)-猫眼课题宝

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

项目类别：

财政年份：

2023

资助国家：

美国

项目状态：

未结题

起止时间：

2023-08-01 至 2028-07-31

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

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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.

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