Clinical advancement of a novel AAV lung gene therapy platform

新型AAV肺部基因治疗平台的临床进展

• 批准号: 549701-2020
• 负责人: Wootton, Sarah
• 金额: $ 15.15万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Collaborative Health Research Projects
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=699048
• 关键词: Clinical; advancement; novel; AAV; lung

Monogenic lung diseases (MLDs) include a variety of disorders that cause chronic lung disease. These diseases often begin in early childhood, lead to respiratory failure and early death, and have few targeted therapies. Surfactant protein deficiencies are a group of severe MLDs caused by mutations in the genes encoding for surfactant proteins A, B, C, and D as well as the ATP-binding cassette sub-family A member 3 (ABCA3). Surfactant protein B (SPB) deficiency is the most severe, leading to respiratory failure after full-term birth. Treatment with exogenous surfactant provides only transient improvement and without lung transplantation, SPB is lethal within the first year of life. MLDs are amenable to targeted delivery of viral vectors via intratracheal administration. Further, as SPB only affects the lungs, targeted delivery of gene therapy to the respiratory tract should be sufficient to treat this disease. We have engineered an innovative viral vector (AAV6.2FF) to treat SPB. AAV6.2FF selectively transduces alveolar type II cells (AT2) cells that produce surfactant and leads to rapid expression of SPB. Our compelling preliminary data in SPB-conditional knockout mice (Kang et al., in revision at Nat Commun) shows that AAV6.2FF efficiently transduces AT2 cells, delivers SPB to the lungs, and dramatically improves lung function and survival. These results demonstrate the promise of AAV6.2FF to treat, and potentially cure, SPB. Our goal is to advance AAV6.2FF gene therapy to clinical trials for the treatment of a variety of MLDs. We will expand our lung gene therapy platform to achieve the following objectives: 1.Evaluate safety and transducing efficiency of AAV6.2FF in neonatal lambs 2.Extend the therapeutic application of AAV6.2FF to other MLDs By combining our expertise in viral vectors, lung biology, and stem cells we aim to develop a variety of clinical trial-ready AAV6.2FF vectors that will transform the treatment of MLDs.

单基因肺病 (MLD) 包括多种导致慢性肺病的疾病 疾病。这些疾病通常始于儿童早期，导致呼吸衰竭和早期 致死，而且很少有针对性的治疗。表面活性剂蛋白质缺乏是一组严重的 由编码表面活性蛋白 A、B、C 和 D 的基因突变引起的 MLD 以及 ATP 结合盒亚家族 A 成员 3 (ABCA3)。表面活性蛋白B (SPB) 缺乏是最严重的，导致足月出生后呼吸衰竭。 使用外源性表面活性剂治疗只能提供短暂的改善，并且不会对肺部产生影响。 移植后，SPB 在生命的第一年内是致命的。 MLD 适合有针对性的 通过气管内给药递送病毒载体。此外，由于 SPB 只影响 肺部，针对呼吸道的基因治疗应该足以治疗 这种病。我们设计了一种创新的病毒载体 (AAV6.2FF) 来治疗 SPB。 AAV6.2FF 选择性转导产生表面活性剂和的肺泡 II 型细胞 (AT2) 细胞 导致 SPB 快速表达。我们在 SPB 条件中令人信服的初步数据 基因敲除小鼠（Kang 等人，Nat Commun 修订中）表明 AAV6.2FF 有效 转导 AT2 细胞，将 SPB 输送至肺部，并显着改善肺功能 生存。这些结果证明了 AAV6.2FF 治疗并可能治愈以下疾病的前景： SPB。我们的目标是将 AAV6.2FF 基因疗法推进临床试验，用于治疗 各种MLD。我们将扩展我们的肺基因治疗平台以实现以下目标 目标： 1.评估AAV6.2FF在新生羔羊中的安全性和转导效率 2.将AAV6.2FF的治疗应用扩展到其他MLD 通过结合我们在病毒载体、肺生物学和干细胞方面的专业知识，我们的目标是开发一种 各种可供临床试验使用的 AAV6.2FF 载体将改变 MLD 的治疗方法。