Harris Ashlee W, Scott Rod C, Butchbach Matthew E R
Division of Neurology, Nemours Children's Hospital Delaware, Wilmington, DE, USA.
Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA.
Sci Rep. 2025 Aug 7;15(1):28866. doi: 10.1038/s41598-025-12194-1.
Spinal muscular atrophy (SMA) is characterized by degeneration of spinal motor neurons and is a leading genetic cause of pediatric death worldwide. SMA results from the loss of or pathological variant in the survival motor neuron 1 (SMN1) gene. Disease severity is dependent on the number of copies of the orthologous SMN2 gene, which is nearly identical to SMN1 except for some key nucleotide differences. As disease severity is inversely related to SMN2 copy number, most SMA therapeutics trials have focused on identifying ways to increase SMN2 expression at different levels of gene regulation. Other studies have investigated compounds which protect affected motor neurons and their target muscles in an SMN-independent manner. In this study, we examined the therapeutic efficacy of the effect of a combination regimen of the SMN2 inducer D156844 and the neuroprotective agent AR42 (REC-2282) on the disease progression and survival in the SMNΔ7 SMA mouse model. The dual administration of D156844 and AR42 results in an additive improvement in the survival of these mice as well as delaying disease endstage. Additionally, coadministration of D156844 and AR42 produced improvements in motor phenotype in SMNΔ7 SMA mice. This study provides further evidence underlying the potential benefit of a combination therapeutics approach to treating SMA.
脊髓性肌萎缩症（SMA）的特征是脊髓运动神经元退化，是全球小儿死亡的主要遗传原因。SMA是由生存运动神经元1（SMN1）基因的缺失或病理性变异引起的。疾病严重程度取决于直系同源SMN2基因的拷贝数，除了一些关键核苷酸差异外，SMN2与SMN1几乎相同。由于疾病严重程度与SMN2拷贝数呈负相关，大多数SMA治疗试验都集中在确定在不同基因调控水平上增加SMN2表达的方法。其他研究调查了以不依赖SMN的方式保护受影响的运动神经元及其靶肌肉的化合物。在本研究中，我们研究了SMN2诱导剂D156844和神经保护剂AR42（REC - 2282）联合方案对SMNΔ7 SMA小鼠模型疾病进展和存活的治疗效果。D156844和AR42的联合给药导致这些小鼠的存活率有相加性提高，同时延缓疾病终末期。此外，D156844和AR42的共同给药使SMNΔ7 SMA小鼠的运动表型得到改善。本研究为联合治疗方法治疗SMA的潜在益处提供了进一步的证据。
