Gene Therapy to Treat Ethanol-induced Osteoporosis Associated with Aldehyde Dehydrogenase 2 Deficiency

基因疗法治疗与乙醛脱氢酶 2 缺乏相关的乙醇诱发的骨质疏松症

基本信息

批准号：
10010871
负责人：
RONALD G CRYSTAL
金额：
$ 25.2万
依托单位：
LEXEO THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10010871
关键词：
Acetaldehyde Adult Adverse event Affect Alcohol consumption Alcohols Aldehydes Alleles Asians Biotechnology Child Chronic Clinical Clinical Research Clinical Trials Code Collaborations Collagen Crystallization Cyclophosphamide Data Dependovirus Development Dominant-Negative Mutation Dose Enzymes Ethanol Ethanol Metabolism Female Femur Gene Transfer Genes Glutamic Acid Goals Hereditary Disease Heterozygote High Prevalence Hip Fractures Histology Homozygote Human Immunity Incidence Individual Investigational New Drug Application Jansky-Bielschowsky Disease Knock-in Mouse Knockout Mice Laboratories Liver Lysine Macaca mulatta Mediating Medical Modeling Mus Mutation Osteoblasts Osteocalcin Osteogenesis Osteopenia Osteoporosis Oxides Panthera leo Periodicity Phase Phenotype Population Positioning Attribute Prevention Preventive therapy Proteins Risk Safety Serotyping Serum Small Business Technology Transfer Research Stress Technology Therapeutic Thick Time Toxic effect Toxicology Type I Procollagen Variant Wild Type Mouse adeno-associated viral vector aldehyde dehydrogenases bone chronic alcohol ingestion clinical phenotype compliance behavior cortical bone crosslink drinking drinking water effective therapy gene therapy gene transfer vector high risk improved in vivo intravenous administration male man meetings molecular phenotype mouse model mutant prevent progenitor substantia spongiosa tomography vector

项目摘要

Abstract. LEXEO Therapeutics, LLC, is an early stage biotechnology company focused on using in vivo gene therapy technologies to treat hereditary disorders of unmet medical need. LEXEO is developing an in vivo gene therapy strategy to mitigate the high risk for osteoporosis in individuals with aldehyde dehydro- genase 2 (ALDH2) deficiency, a hereditary disorder affecting 8% of the world population, and 35-45% of people of East Asian background. ALDH2 is a key enzyme for ethanol metabolism; with ethanol ingestion, mutations that reduce the oxidizing ability of the enzyme result in systemic accumulation of toxic acetalde- hyde. The most common variant is the ALDH2*2 allele (glutamic acid-to-lysine substitution, E487K). Heter- ozygotes have <50% ALDH2 enzymatic activity; homozygotes have <4% due to the dominant negative function of the mutant protein in the tetrameric enzyme. The combination of acetaldehyde and ethanol suppresses early osteoblast progenitor formation, leading to decreased bone formation and osteoporosis. Individuals with ALDH2 deficiency who drink alcohol have an increased risk for osteoporosis and hip frac- ture. Current forms of osteoporosis therapy have limitations in duration of effective therapy, compliance and toxicities, making the development of a specific means to prevent or reverse osteoporosis associated with ALDH2 deficiency desirable. LEXEO’s proposed therapy is a one-time intravenous administration of LEX06 (AAVrh.10hALDH2), an adeno-associated virus serotype 10 gene transfer vector expressing the normal human ALDH2 coding sequence. In collaboration with the Crystal laboratory at Weill Cornell, LEXEO has assessed osteopenia in 2 mouse models of ALDH2 deficiency. After chronic ethanol inges- tion, these models have high serum acetaldehyde levels and develop a striking osteopenia phenotype quantified by microcomputed tomography (µCT) and histology with significantly lower bone volume/total volume, cortex thickness, trabecular number and thickness, and increased trabecular space. When pre- treated with intravenous administration of LEX06, there was remarkable prevention of these bone abnor- malities, demonstrating that LEX06 can prevent the development of osteopenia associated with ALDH2 deficiency and chronic ethanol ingestion. The goal of this Phase I STTR, is to demonstrate that LEX06 will also correct the osteopenia in ALDH2 deficient mice after they have been chronically administered etha- nol and have established osteopenia, documenting that LEX06 therapy can be a treatment of ALDH2 defi- cient-associated osteopenia. We propose the following. Aim 1. To evaluate the hypothesis that LEX06 (AAVrh.10hALDH2) therapy will reverse ethanol-induced osteopenia in ALDH2E487K+/+ mice. With this effi- cacy data, LEXEO will be ready to move to a phase II STTR to have a pre-IND meeting with the FDA, manufacture clinical grade LEX06, carry out formal safety/toxicology studies and submit an Investigational New Drug application to initiate a clinical trial.

抽象的。 Lexeo Therapeutics，LLC是一家早期生物技术公司，专注于使用体内基因疗法技术治疗未满足的医学需求的遗传疾病。 Lexeo正在开发体内基因治疗策略以减轻醛脱氢醛个体的骨质疏松症的高风险遗传2（ALDH2）缺乏症，一种影响世界人口8％的遗传疾病，35-45％东亚背景的人。 ALDH2是乙醇代谢的关键酶。随着乙醇的摄取，降低酶氧化能力的突变会导致有毒乙酸酯的全身积累海德。最常见的变体是Aldh2*2等位基因（谷氨酸到赖氨酸取代，E487K）。异臭氧具有<50％的ALDH2酶活性；纯合子由于显性负而<4％乙醛和乙醇的组合抑制早期成骨细胞祖细胞的形成，导致骨形成和骨质疏松症减少。饮酒的ALDH2缺乏症患者患骨质疏松症和髋关节骨气的风险增加 ture。骨质疏松疗法的当前形式在有效治疗的持续时间内有局限性和毒性，制定一种预防或逆转骨质疏松症相关的特定手段与ALDH2缺乏症相关。 Lexeo的拟议治疗是一次性的静脉内给药 LEX06（AAVRH.10HALDH2），一种与腺相关的病毒血清型10基因转移载体表达正常的人ALDH2编码序列。与威尔·康奈尔（Weill Cornell）的水晶实验室合作 Lexeo评估了2种ALDH2缺乏小鼠模型中的骨质减少症。慢性乙醇inges- 这些模型具有高血清乙醛水平，并发展出惊人的骨质减少表型通过微型层析成像（µCT）和组织学量化，骨体积/总量明显降低体积，皮层厚度，小梁数量和厚度以及小梁空间增加。当预先通过静脉内给药LEX06治疗，可以明显预防这些骨骼病人表明LEX06可以防止与Aldh2相关的骨质减少症的发展缺乏和慢性乙醇摄入。该阶段I STTR的目标是证明Lex06将还要纠正ALDH2缺乏小鼠的骨质减少症。 NOL并已经建立了骨质减少症，证明LEX06治疗可以作为Aldh2 fefi的治疗相关的骨质减少症。我们建议以下内容。目的1。评估LEX06的假设（AAVRH.10HALDH2）疗法将逆转乙醇诱导的AldH2E487K+/+小鼠的骨质减少症。通过这种努力 - CACY数据，Lexeo将准备转到II期STTR，与FDA进行预先开会，制造临床级LEX06，进行正式的安全/毒理学研究并提交研究新药物应用启动临床试验。