α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson's disease
α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson's disease
复制标题
DOI：
10.1172/jci.insight.135633
复制
发表时间：
2021-03-08
期刊：
影响因子：
8
通讯作者：
Paumier, Katrina L.
中科院分区：
文献类型：
--
作者：
Cole, Tracy A.;Zhao, Hien;Paumier, Katrina L.
帕金森病（PD）是一种流行的神经退行性疾病，目前尚无获批的疾病修饰疗法。编码α-突触核蛋白（aSyn）蛋白的SNCA基因的增殖、突变和单核苷酸多态性可导致或增加PD的风险。aSyn的细胞内积累是PD的病理标志。总之，aSyn产生的减少可以为PD提供疾病改善疗法。我们表明，反义寡核苷酸（ASO）减少生产的aSyn在啮齿动物预制原纤维（PFF）模型的PD。减少的aSyn产生导致预防和消除已建立的aSyn病理，并预防多巴胺能细胞功能障碍。此外，我们通过表征在体内有效抑制人SNCA转录的人SNCA靶向ASO来解决该方法的翻译潜力。我们证明了人SNCA ASO在整个非人灵长类动物脑中的广泛活性和分布以及aSyn脑脊液（CSF）水平的相应降低。综上所述，这些数据表明，通过抑制aSyn的产生，有可能逆转已建立的病理学;因此，这些数据支持SNCA ASO作为PD和相关突触核蛋白病的潜在疾病改善疗法的开发。
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 alpha-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.