Clinical advancement of a novel AAV lung gene therapy platform

单基因肺病(MLD)包括导致慢性肺部疾病的各种疾病。 疾病。这些疾病通常始于儿童早期，导致呼吸衰竭和早期 死亡，而且几乎没有针对性的治疗方法。表面活性物质蛋白缺乏是一组严重的 由编码表面活性蛋白A、B、C和D AS的基因突变引起的MLD 以及ATP结合盒A亚家族成员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物质治疗只能提供短暂的改善，并且没有肺 移植，SPB在生命的第一年内是致命的。MLD容易成为靶子 通过气管内给药传递病毒载体。此外，由于SPB只影响 肺，靶向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选择性地转导肺泡II型细胞(AT2)产生表面活性物质和 导致SPB的快速表达。我们令人信服的SPB初步数据-有条件的 基因敲除小鼠(Kang等人，在NAT Commun的修订中)表明AAV6.2FF有效 转导AT2细胞，将SPB输送到肺部，显著改善肺功能和 生死存亡。这些结果表明AAV6.2FF有望治疗并有可能治愈 SPB。我们的目标是将AAV6.2FF基因疗法推进到临床试验中，用于治疗A MLD的种类繁多。我们将扩大我们的肺基因治疗平台，以实现以下目标 目标： 1.评价AAV6.2FF在新生羔羊体内的安全性和转导效率 2.将AAV6.2FF的治疗应用推广到其他多器官功能障碍 通过结合我们在病毒载体、肺部生物学和干细胞方面的专业知识，我们的目标是开发一种 多种临床试验就绪的AAV6.2FF载体，将改变MLDs的治疗。

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.