Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
Michigan State University, Grand Rapids, Michigan, USA.
JCI Insight. 2021 Mar 8;6(5):135633. doi: 10.1172/jci.insight.135633.
Parkinson's disease (PD) is a prevalent neurodegenerative disease with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding α-synuclein (aSyn) protein, either cause or increase risk for PD. Intracellular accumulations of aSyn are pathological hallmarks of PD. Taken together, reduction of aSyn production may provide a disease-modifying therapy for PD. We show that antisense oligonucleotides (ASOs) reduce production of aSyn in rodent preformed fibril (PFF) models of PD. Reduced aSyn production leads to prevention and removal of established aSyn pathology and prevents dopaminergic cell dysfunction. In addition, we address the translational potential of the approach through characterization of human SNCA-targeting ASOs that efficiently suppress the human SNCA transcript in vivo. We demonstrate broad activity and distribution of the human SNCA ASOs throughout the nonhuman primate brain and a corresponding decrease in aSyn cerebral spinal fluid (CSF) levels. Taken together, these data suggest that, by inhibiting production of aSyn, it may be possible to reverse established pathology; thus, these data support the development of SNCA ASOs as a potential disease-modifying therapy for PD and related synucleinopathies.
帕金森病（PD）是一种常见的神经退行性疾病，目前尚无批准的疾病修饰疗法。编码α-突触核蛋白（aSyn）的 SNCA 基因的扩增、突变和单核苷酸多态性，要么导致 PD，要么增加 PD 的风险。aSyn 的细胞内积累是 PD 的病理标志。总之，减少 aSyn 的产生可能为 PD 提供一种疾病修饰疗法。我们表明，反义寡核苷酸（ASOs）可减少 PD 预形成纤维（PFF）模型中 aSyn 的产生。减少 aSyn 的产生可预防和清除已建立的 aSyn 病理学并防止多巴胺能细胞功能障碍。此外，我们通过对人类 SNCA 靶向 ASO 的特征描述来解决该方法的转化潜力，这些 ASO 可有效地在体内抑制人类 SNCA 转录本。我们证明了人类 SNCA ASO 在整个非人类灵长类动物大脑中的广泛活性和分布，以及相应的 aSyn 脑脊液（CSF）水平降低。总之，这些数据表明，通过抑制 aSyn 的产生，可能有可能逆转已建立的病理学；因此，这些数据支持将 SNCA ASO 作为 PD 和相关突触核蛋白病的潜在疾病修饰疗法进行开发。
