Clinical advancement of a novel AAV lung gene therapy platform

单基因肺疾病（MLDs）包括引起慢性肺病的多种疾病。这些疾病通常开始于儿童早期，导致呼吸衰竭和早死，并且几乎没有靶向治疗。表面活性蛋白缺乏症是由表面活性蛋白A、B、C和D以及ATP结合盒亚家族A成员3（ABCA 3）的基因突变引起的一组严重MLD。表面活性蛋白B（SP B）缺乏症是最严重的一种，可导致足月出生后呼吸衰竭，外源性表面活性物质治疗只能提供短暂的改善，如不进行肺移植，SP B在出生后一年内是致命的。MLD适合于通过肠道内给药靶向递送病毒载体。此外，由于SPB仅影响肺，因此将基因治疗靶向递送至呼吸道应足以治疗该疾病。我们设计了一种新的病毒载体（AAV6.2FF）来治疗SPB。AAV6.2FF选择性地转导肺泡II型细胞（AT 2），该细胞产生表面活性剂并导致SPB的快速表达。我们在SPB-条件性敲除小鼠中的令人信服的初步数据（Kang等人，在Nat Commun的修订中）显示AAV6.2FF有效地转导AT 2细胞，将SPB递送到肺，并显著改善肺功能和存活。这些结果证明了AAV6.2FF治疗和潜在治愈SPB的前景。我们的目标是将AAV6.2FF基因治疗推进到临床试验，用于治疗各种MLD。我们将扩大我们的肺基因治疗平台，以实现以下目标：1.评估AAV6.2FF在新生儿肺部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临床试验准备的AAV6.2FF载体，这将改变MLD的治疗。

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.