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
基本信息
- 批准号:549701-2020
- 负责人:
- 金额:$ 7.12万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Collaborative Health Research Projects
- 财政年份:2022
- 资助国家:加拿大
- 起止时间:2022-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Monogenic lung diseases (MLDs) include a variety of disorders that cause chronic lungdisease. These diseases often begin in early childhood, lead to respiratory failure and earlydeath, and have few targeted therapies. Surfactant protein deficiencies are a group of severeMLDs caused by mutations in the genes encoding for surfactant proteins A, B, C, and D aswell 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 lungtransplantation, SPB is lethal within the first year of life. MLDs are amenable to targeteddelivery of viral vectors via intratracheal administration. Further, as SPB only affects thelungs, targeted delivery of gene therapy to the respiratory tract should be sufficient to treatthis 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 andleads to rapid expression of SPB. Our compelling preliminary data in SPB-conditionalknockout mice (Kang et al., in revision at Nat Commun) shows that AAV6.2FF efficientlytransduces AT2 cells, delivers SPB to the lungs, and dramatically improves lung function andsurvival. 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 avariety of MLDs. We will expand our lung gene therapy platform to achieve the followingobjectives:1.Evaluate safety and transducing efficiency of AAV6.2FF in neonatal lambs2.Extend the therapeutic application of AAV6.2FF to other MLDsBy combining our expertise in viral vectors, lung biology, and stem cells we aim to develop avariety of clinical trial-ready AAV6.2FF vectors that will transform the treatment of MLDs.
单基因肺病 (MLD) 包括多种引起慢性肺病的疾病。这些疾病通常始于儿童早期,导致呼吸衰竭和过早死亡,并且很少有针对性的治疗方法。表面活性剂蛋白缺乏症是由编码表面活性剂蛋白 A、B、C 和 D 以及 ATP 结合盒亚家族 A 成员 3 (ABCA3) 的基因突变引起的一组严重 MLD。表面活性剂蛋白 B (SPB) 缺乏最为严重,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,如果不进行肺移植,SPB 在出生后第一年内就会致命。 MLD 适合通过气管内给药来靶向递送病毒载体。此外,由于 SPB 仅影响肺部,因此向呼吸道进行靶向基因治疗应该足以治疗这种疾病。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并导致 SPB 快速表达的 II 型肺泡细胞 (AT2) 细胞。我们在 SPB 条件敲除小鼠中获得的令人信服的初步数据(Kang 等人,在 Nat Commun 修订中)表明,AAV6.2FF 有效转导 AT2 细胞,将 SPB 递送至肺部,并显着改善肺功能和存活率。这些结果证明了 AAV6.2FF 治疗并可能治愈 SPB 的前景。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部基因治疗平台,以实现以下目标: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,我们的目标是开发各种可供临床试验使用的 AAV6.2FF 载体,这将改变 AAV6.2FF 的治疗方法。 MLD。
项目成果
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