Gene Therapy for Surfactant Disorders

在出生时，一些婴儿由于肺部无法充气而无法呼吸，这通常是由于遗传疾病导致缺乏表面活性蛋白。表面活性剂形成一层薄膜，覆盖在肺部的气体交换表面。这是为了防止肺萎陷。几种蛋白质对正常的表面活性剂代谢至关重要，例如，表面活性剂蛋白B、表面活性剂蛋白C和ABCA 3。由于基因突变，这些蛋白质的缺失或功能降低会导致严重的呼吸窘迫。受影响的婴儿的前景可能很差，开发治疗方法的进展一直很缓慢，因为大多数此类疾病非常罕见。在我的哲学博士项目中，我正在研究表面活性物质紊乱的基因治疗。其原理是使用腺相关病毒（AAV）作为递送载体，将正确的遗传信息递送到肺中称为肺泡II型细胞的特定细胞，肺泡II型细胞是表面活性剂代谢的部位。AAV是一种非致病性病毒，已知其能够感染不同的靶组织，在基因治疗应用中具有良好的安全性。如果递送的基因在肺中长期表达，则这种方法具有治疗表面活性物质障碍的潜力。重要的是，即使是部分校正也可能有好处，例如通过延长可以提供肺移植的窗口。

At birth, some babies fail to breathe due to a failure to inflate their lungs and often this is due to genetic diseases resulting in a lack of surfactant protein. Surfactant forms a thin film that covers the gas exchange surface in the lung. It is required to prevent the lung from collapse. Several proteins are crucial to normal surfactant metabolism, for example, surfactant protein B, surfactant protein C and ABCA3. Absence or reduced function of such proteins due to genetic mutation leads to severe respiratory distress. The outlook for affected babies can be poor and progress in developing treatments has been slow as the majority of such diseases are very rare. In my DPhil project I am investigating gene therapy for surfactant disorders. The principle is to deliver the correct genetic information to specific cells in the lung called alveolar type II cells, the site of surfactant metabolism, using adeno-associated virus (AAV) as a vehicle for delivery. AAV is a non-pathogenic virus which is known for its ability to infect different target tissues with a good safety profile in gene therapy applications. If the delivered genes are expressed long-term in the lung this approach has the potential to treat surfactant disorders. Importantly, even partial correction may have a benefit, for example by extending the window in which lung transplantation could be offered.