Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA.
Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA.
Gene Ther. 2019 Aug;26(7-8):287-295. doi: 10.1038/s41434-019-0085-4. Epub 2019 Jun 26.
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is characterized by the deterioration of alpha motor neurons in the brainstem and spinal cord. Currently, there is no cure for SMA, which calls for an urgent need to explore affordable and effective therapies and to maximize patients' independence and quality of life. Adeno-associated virus (AAV) vector, one of the most promising and well-investigated vehicles for delivering transgenes, is a compelling candidate for gene therapy. Some of the hallmarks of AAVs are their nonpathogenicity, inability to incur an immune response, potential to achieve robust transgene expression, and varied tropism for several tissues of the body. Recently, these features were harnessed in a clinical trial conducted by AveXis in SMA patients, where AAV9 was employed as a vehicle for one-time administration of the SMN gene, the causative gene in SMA. The trial demonstrated remarkable improvements in motor milestones and rates of survival in the patients. This review focuses on the advent of SMA gene therapy and summarizes different preclinical studies that were conducted leading up to the AAV9-SMA trial in SMA patients.
脊髓性肌萎缩症（SMA）是婴儿死亡的主要遗传原因，其特征是脑干和脊髓中的 alpha 运动神经元恶化。目前，SMA 尚无治愈方法，因此迫切需要探索负担得起且有效的治疗方法，并最大限度地提高患者的独立性和生活质量。腺相关病毒（AAV）载体是一种最有前途和研究最充分的转染基因载体，是基因治疗的理想候选者。AAV 的一些特点包括非致病性、不能引起免疫反应、实现强大的转基因表达的潜力以及对身体多种组织的广泛嗜性。最近，这些特性在 AveXis 公司对 SMA 患者进行的临床试验中得到了利用，其中 AAV9 被用作一次性给予 SMN 基因（SMA 的致病基因）的载体。该试验表明，患者的运动里程碑和存活率显著提高。本综述重点介绍了 SMA 基因治疗的出现，并总结了导致该试验的不同临床前研究。
