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.

摘要：LEXEO Therapeutics, LLC 是一家专注于体内应用的早期生物技术公司。 LEXEO 正在开发一种用于治疗未满足医疗需求的遗传性疾病的基因治疗技术。体内基因治疗策略可降低醛脱氢个体骨质疏松症的高风险基因酶 2 (ALDH2) 缺乏症是一种遗传性疾病，影响世界人口的 8%，以及 35-45% 的人东亚背景的人 ALDH2 是乙醇代谢的关键酶；降低酶氧化能力的突变导致有毒乙醛的全身积累最常见的变体是 ALDH2*2 等位基因（谷氨酸至赖氨酸取代，E487K）。由于显性失活，合子的 ALDH2 酶活性 <50%；纯合子的 ALDH2 酶活性 <4%；突变蛋白在四聚体酶中的功能乙醛和乙醇的结合。抑制早期成骨细胞祖细胞的形成，导致骨形成减少和骨质疏松。缺乏 ALDH2 的人饮酒会增加骨质疏松和髋部骨折的风险。目前的骨质疏松症治疗形式在有效治疗持续时间、依从性方面存在局限性。和毒性，使得开发预防或逆转骨质疏松症相关的特定方法 LEXEO 提出的治疗方法是一次性静脉注射 ALDH2 缺乏症。 LEX06 (AAVrh.10hALDH2)，一种腺相关病毒血清型 10 基因转移载体，表达正常人类 ALDH2 编码序列与威尔康奈尔大学水晶实验室合作， LEXEO 评估了 2 种 ALDH2 缺乏症小鼠模型在长期摄入乙醇后的骨质减少情况。化，这些模型具有高血清乙醛水平并形成显着的骨质减少表型通过显微计算机断层扫描 (μCT) 和组织学进行量化，骨量/总骨量显着降低体积、皮质厚度、小梁数量和厚度以及小梁间隙的增加。通过静脉注射 LEX06 进行治疗，可以显着预防这些骨异常。表明 LEX06 可以预防与 ALDH2 相关的骨质减少的发展第一阶段 STTR 的目标是证明 LEX06 能够预防缺乏症和慢性乙醇摄入。还可以纠正 ALDH2 缺陷小鼠长期服用 etha 后的骨质减少情况。没有，并且已确定骨质减少，证明 LEX06 疗法可以治疗 ALDH2 缺乏症我们提出以下目标：评估 LEX06 的假设。 (AAVrh.10hALDH2) 疗法将逆转 ALDH2E487K+/+ 小鼠中乙醇诱导的骨质减少。 cacy 数据显示，LEXEO 将准备好进入 II 期 STTR，与 FDA 举行 IND 前会议，生产临床级 LEX06，进行正式的安全性/毒理学研究并提交研究报告新药申请启动临床试验。