Oxidation-resistant Anti-protease Therapy

抽象的。LEXEO Treateutics，LLC是一家专注于使用基因的早期生物技术公司 保护脆弱器官免受氧化应激的治疗技术。LEX01是第一款LEXEO产品，是一款 班级第一名，新一代基因疗法治疗常染色体α1抗胰蛋白酶(AAT)缺乏症 与低血清AAT水平相关的隐性遗传性疾病。AAT(SERPINA1)，一个52 kDa的丝氨酸 由肝脏产生的抗蛋白酶，保护肺免受炎症释放的蛋白水解酶的影响 细胞。在AAT缺乏症中，肺容易受到炎症释放的蛋白水解酶的破坏。 使肺退化，导致肺气肿的交配细胞。AAT缺乏症目前的治疗方法是 每周输注从混合人血浆中提纯的AAT。AAT缺乏症的基因治疗 承诺一次给药将产生足够数量的AAT来保护永久性肺- 帐篷基础上，取消每周的AAT蛋白质治疗。第一代基因治疗策略正在被淘汰 腺相关病毒基因转移载体治疗AAT缺乏症的研究进展 人AAT编码序列在体内通过多种途径传递。这些战略的致命弱点是它的意义-- AAT分子对氧化剂的活性。人AAT的活性部位包括Met358，具有2°的构象. 乘坐Met351航班。当被氧化时(例如，被香烟烟雾、炎性细胞产物、环境污染)， AAT无效，不能抑制其主要靶点--中性粒细胞弹性蛋白酶。LEX01，设计为 编码弹性蛋白酶抑制、抗氧化的人AAT的AAV载体解决了这一问题。 用Val或Leu取代Met358位和/或Met351位的Lem，使AAT分子氧化. 抵抗，但仍保持其作为抗弹力酶的功能。这是一个快速跟踪应用程序，目标是- ING临床试验-在3年内准备就绪。这些目标的成功实现将使乐视对 生物技术、制药和/或风险投资。第一阶段，目标1。使用正常的M1(A213)AAT编码 序列作为碱基，评估位置351和358的Met、Leu和Val的组合，以确定 用于LEX01的最佳中性粒细胞弹性蛋白酶抑制、抗氧化形式的AAT。第一阶段，目标2。 确定实验动物胸腔内注射LEX01可导致持续的、高水平的 人抗氧化性AAT在血清和肺上皮衬里液中的ELS。第一阶段，目标三。有一个预赛- IND与FDA就LEX01开发计划举行会议。第二阶段，目标1.生产和验证 GMP临床分级为LEX01，并在实验动物中证明在人体试验中使用是安全的。 第二阶段，目标2。开发和验证用于临床研究的分析方法。向FDA提交一份 IND允许启动LEX01治疗AAT缺乏症的I期临床研究。

Abstract. LEXEO Therapeutics, LLC, is an early stage biotechnology company focused on using gene therapy technologies to protect vulnerable organs from oxidant stress. LEX01, the 1st LEXEO product, is a 1st in class, next generation gene therapy treatment for alpha 1-antitrypsin (AAT) deficiency, an autosomal recessive hereditary disorder associated with low serum levels of AAT. AAT (SERPINA1), a 52 kDa serine antiprotease produced by the liver, protects the lung from proteolytic enzymes released by inflammatory cells. In AAT deficiency, the lung is vulnerable to destruction by proteolytic enzymes released by inflam- matory cells that degrade the lung, resulting in emphysema. AAT deficiency is currently treated with weekly infusions of AAT purified from pooled human plasma. Gene therapy for AAT deficiency holds the promise that a single administration will generate sufficient amounts of AAT to protect the lung on a persis- tent basis, obviating weekly AAT protein therapy. First generation gene therapy strategies are under de- velopment to treat AAT deficiency using adenoassociated virus (AAV) gene transfer vectors to deliver the human AAT coding sequence in vivo by various routes. The Achilles heel of these strategies is the sensi- tivity of the AAT molecule to oxidants. The active site of human AAT includes Met358, with a 2° contribu- tion by Met351. When oxidized (e.g., by cigarette smoke, inflammatory cell products, ambient pollution), AAT is rendered ineffective and cannot inhibit neutrophil elastase, its primary target. LEX01, designed as an AAV vector coding for an elastase-inhibiting, oxidation-resistant human AAT, solves this prob- lem with substitution at Met358 and/or Met351 with Val or Leu to render the AAT molecule oxidation re- sistant, yet maintaining its function as an anti-elastase. This is a Fast Track application with the goal of be- ing clinical trial-ready within 3 yr. Successful completion of these aims will make LEXEO attractive for biotech, pharma and/or venture investment. Phase I, Aim 1. Using the normal M1(A213) AAT coding sequence as a base, assess combinations of Met, Leu and Val at positions 351 and 358 to determine the optimal neutrophil elastase inhibiting, oxidation resistant form of AAT to use in LEX01. Phase I, Aim 2. Determine that intrapleural administration of LEX01 to experimental animals results in persistent, high lev- els of oxidation-resistant human AAT in serum and lung epithelial lining fluid. Phase I, Aim 3. Have a pre- IND meeting with the FDA regarding the LEX01 development plan. Phase II, Aim 1. Produce and validate GMP clinical grade LEX01 and demonstrate in experimental animals it is safe to use in a human trial. Phase II, Aim 2. Develop and validate the assays to be used in the clinical study. Submit to the FDA an IND permitting initiation of a phase I clinical study of LEX01 for AAT deficiency.