LEAD PROJECT 1: PHENYLKETONURIA (PKU)

牵头项目 1：苯丙酮尿症 (PKU)

基本信息

批准号：
10668618
负责人：
Kiran Musunuru
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/10668618
关键词：
Address Adenine Anaphylaxis Animal Model Biodistribution Blood Classical phenylketonuria Defect Diet Dietary Intervention Disease Dose Drug Kinetics Drug Packaging Enzymes Europe Felis catus Funding Genes Goals Guide RNA Hepatocyte High Prevalence Human Hyperphenylalaninaemias Impaired cognition Impairment Inherited Injectable Investigational Drugs Investigational New Drug Application Lead Link Liver Mediating Medical Metabolic Metabolic Diseases Middle East Modeling Mus Mutation Oral Outcome Pathogenicity Patients Pharmaceutical Preparations Pharmacology and Toxicology Phase I/II Clinical Trial Phenotype Phenylalanine Phenylalanine Hydroxylase Phenylketonurias Population Risk Russia Therapeutic Toxic effect United States Food and Drug Administration Variant Work amino acid metabolism autosome base editing base editor causal variant cofactor cognitive development curative treatments enzyme therapy gallium arsenide genome editing humanized mouse lead optimization lipid nanoparticle mutation correction neuropsychiatry neurotoxic neurotoxicity nonhuman primate pharmacologic postnatal pre-Investigational New Drug meeting prenatal prime editing prime editor response therapeutic genome editing transition mutation

项目摘要

PROJECT SUMMARY Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the gene encoding phenylalanine hydroxylase (PAH), resulting in the accumulation of phenylalanine (Phe) to neurotoxic levels. Among the five most frequently occurring pathogenic PAH variants worldwide is the c.842C>T (P281L) mutation, which is amenable to adenine base editing. The current treatment options have significant limitations—a strict low-Phe diet to which many patients find it difficult to adhere, and a daily injectable enzyme therapy with a substantial risk of anaphylaxis. Lead Project 1 will focus on a lipid nanoparticle (LNP)-based adenine base editing treatment for PKU in patients with the P281L variant, with the aim to file an IND application by the end of the five-year funding period and begin a phase 1/2 clinical trial soon afterwards.

项目概要苯丙酮尿症 (PKU) 是一种常染色体隐性遗传疾病，由编码基因突变引起苯丙氨酸羟化酶（PAH），导致苯丙氨酸（Phe）积累至神经毒性水平。全球五种最常见的致病性 PAH 变异中，c.842C>T (P281L) 突变为目前的治疗方案有很大的局限性——严格的限制。许多患者发现难以坚持的低 Phe 饮食，以及每日注射酶疗法主导项目 1 将重点关注基于脂质纳米颗粒 (LNP) 的腺嘌呤碱。编辑 P281L 变异患者的 PKU 治疗方案，目标是在年底前提交 IND 申请五年资助期结束后不久就开始1/2期临床试验。