Departments of Pediatrics, Neurology & Neurosurgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, Canada.
Children's Hospital of the King's Daughters, Norfolk, VA, United States.
Expert Opin Biol Ther. 2022 Sep;22(9):1075-1090. doi: 10.1080/14712598.2022.2066471. Epub 2022 May 2.
Gene therapy for spinal muscular atrophy (SMA) represents a significant milestone in the treatment of neurologic diseases. SMA is a neurodegenerative disease that results in motor neuron loss because of mutations of the gene, which directs survival motor neuron (SMN) protein production. Onasemnogene abeparvovec, a one-time gene replacement therapy, delivers a functional transgene to restore SMN protein expression. Onasemnogene abeparvovec has demonstrated improved survival and motor milestone achievements for presymptomatic infants and patients with SMA type 1.
This expert review describes the current state of gene therapy for SMA, reviews the mechanism of and clinical experience with onasemnogene abeparvovec, explains future efforts to expand applications of gene therapy for SMA, and provides context for developing gene therapy for other conditions.
Onasemnogene abeparvovec has demonstrated efficacy in clinical trials and, because of this, is a valuable treatment option for patients with symptomatic infantile SMA and those identified by newborn screening. Gene therapy is still in its infancy, and challenges and uncertainties associated with transgene delivery must be addressed. With ongoing development of vector technology, more specific tissue tropism, reduced 'off-target' effects, and an enhanced safety profile will continue to evolve.
脊髓性肌萎缩症（SMA）的基因治疗代表了治疗神经疾病的一个重要里程碑。SMA 是一种神经退行性疾病，由于基因的突变，导致运动神经元丧失，该基因指导生存运动神经元（SMN）蛋白的产生。onasemnogene abeparvovec 是一种一次性基因替代疗法，可传递功能性转基因，以恢复 SMN 蛋白的表达。onasemnogene abeparvovec 已证明可改善症状前婴儿和 1 型 SMA 患者的生存和运动里程碑成就。
本专家评论描述了 SMA 的基因治疗现状，回顾了 onasemnogene abeparvovec 的作用机制和临床经验，解释了为扩大 SMA 基因治疗应用所做的未来努力，并为开发其他疾病的基因治疗提供了背景。
onasemnogene abeparvovec 在临床试验中已显示出疗效，因此，它是有症状的婴儿型 SMA 患者和通过新生儿筛查确定的患者的有价值的治疗选择。基因治疗仍处于起步阶段，必须解决与转基因传递相关的挑战和不确定性。随着载体技术的不断发展，将继续发展更具组织特异性、降低“脱靶”效应和增强安全性的特点。
