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

抽象的。LEXEO Therapeutics，LLC是一家早期生物技术公司，专注于在体内使用 基因治疗技术，以治疗未满足医疗需求的遗传性疾病。LECEO正在开发一种 体内基因治疗策略，以减轻高风险的骨质疏松症的个人与醛酮- ALDH 2缺乏症是一种遗传性疾病，影响8%的世界人口和35-45%的 东亚背景的人。ALDH 2是乙醇代谢的关键酶;随着乙醇摄入， 降低酶氧化能力的突变导致毒性乙醛的全身积累， 海德最常见的变异是ALDH 2 *2等位基因（谷氨酸-赖氨酸取代，E487 K）。异- 卵合子具有<50%的ALDH 2酶活性;由于显性阴性，纯合子具有<4%的ALDH 2酶活性。 突变蛋白在四聚体酶中的功能。乙醛和乙醇的组合 抑制早期成骨细胞祖细胞形成，导致骨形成减少和骨质疏松症。 饮酒的ALDH 2缺乏者患骨质疏松症和髋关节骨折的风险增加。 是的。目前形式的骨质疏松症治疗在有效治疗的持续时间、依从性、有效治疗的持续时间和有效治疗的持续时间方面存在局限性。 和毒性，使得开发一种特定的手段来预防或逆转骨质疏松症相关的 ALDH 2缺乏的人。LEXEO提出的治疗方法是一次性静脉注射 LEX 06（AAVrh.10hALDH2），一种腺相关病毒血清型10基因转移载体，表达 正常人ALDH 2编码序列。与威尔康奈尔大学的水晶实验室合作， LEXEO已在2种ALDH 2缺乏症小鼠模型中评估了骨质减少。在慢性酒精摄入后- 事实上，这些模型具有高的血清乙醛水平，并发展出显著的骨质减少表型 通过微计算机断层扫描（µCT）和组织学定量，骨体积/总骨体积显著降低 体积、皮质厚度、小梁数量和厚度以及增加的小梁间隙。当预- 用静脉内给予LEX 06治疗，对这些骨异常有显著的预防作用， malities，证明了LEX 06可以预防与ALDH 2相关的骨质减少症的发展 缺乏和慢性乙醇摄入。本阶段I STTR的目标是证明LEX 06将 也纠正ALDH 2缺陷小鼠在长期给予乙醇后的骨质减少， nol和已确定的骨质疏松症，记录了LEX 06治疗可以是ALDH 2缺陷的治疗。 与病人相关的骨质减少我们提出以下建议。目标1.为了评估LEX 06 10 hALDH 2）治疗将逆转ALDH 2 E487 K +/+小鼠中乙醇诱导的骨质减少。有了这个效果-- 根据准确的数据，LEXEO将准备进入II期STTR，与FDA举行IND前会议， 生产临床级LEX 06，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。

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.