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

抽象的。LEXEO Treateutics，LLC是一家早期生物技术公司，专注于在体内使用 用于治疗未满足医疗需求的遗传性疾病的基因治疗技术。LexEO正在开发一种In 体内基因治疗策略降低乙醛脱水患者患骨质疏松症的高风险 基因2(ALDH2)缺乏症，一种影响8%世界人口的遗传性疾病，以及35%-45%的 东亚背景的人。ALDH2是乙醇新陈代谢的关键酶；摄入乙醇后， 降低酶的氧化能力的突变会导致有毒乙醛的全身积累- 海德。最常见的变异是ALDH2*2等位基因(谷氨酸到赖氨酸的取代，E487K)。赫特- 合子有50%的ALDH2酶活性；由于显性阴性，纯合子有&lt；4% 突变蛋白在四聚体酶中的作用。乙醛和乙醇的结合 抑制早期成骨细胞前体细胞的形成，导致骨形成减少和骨质疏松。 ALDH2缺乏的人饮酒后患骨质疏松症和髋部骨折的风险增加。 千真万确。目前的骨质疏松症治疗形式在有效治疗的持续时间、依从性方面存在局限性 和毒性，使得制定一种特定的手段来预防或逆转骨质疏松症 ALDH2缺乏症是可取的。LexEO提出的治疗方法是一次性静脉注射 LEX06(AAVRh.10hALDH2)，腺相关病毒血清10型基因转移载体，表达 正常人类ALDH2编码序列。与威尔·康奈尔大学的水晶实验室合作， LeXEO已经在两个ALDH2缺乏的小鼠模型中评估了骨量减少。在慢性酒精中毒之后- 这些模型的血清乙醛水平较高，并出现明显的骨量减少表型。 通过微计算机断层扫描(µCT)和组织学进行量化，骨体积/总骨体积显著降低 体积、皮质厚度、骨小梁数目和厚度、骨小梁间隙增大。当Pre- 静脉注射LEX06对这些骨质疏松症有明显的预防作用。 表明LEX06可以预防与ALDH2相关的骨量减少症的发生 缺乏和长期摄入酒精。此第一阶段STTR的目标是证明LEX06将 并纠正ALDH2缺陷小鼠长期服用乙醇胺后的骨量减少。 NOL和已经建立了骨量减少症，证明LEX06疗法可以治疗ALDH2缺陷。 陈旧性骨质疏松症。我们提出以下建议。目的1.评估LEX06的假设 (AAVRH.10hALDH2)治疗将逆转乙醇诱导的ALDH2 E487K+/+小鼠的骨量减少。有了这样的效果- Cacy Data，LEXEO将准备转移到第二阶段STTR，与FDA举行IND前会议， 制造临床等级LEX06，进行正式的安全/毒理学研究并提交调查报告 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.