Center for Neuroscience and Cell Biology (CNC), Molecular Therapy of Brain Disorders Group, University of Coimbra, Coimbra, Portugal.
Center for Innovative Biomedicine and Biotechnology (CIBB), Vectors, Gene and Cell Therapy Group, University of Coimbra, Coimbra, Portugal.
Nucleic Acid Ther. 2022 Jun;32(3):194-205. doi: 10.1089/nat.2021.0020. Epub 2021 Dec 7.
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by the expansion of a CAG repeat in the gene. This mutation leads to a toxic gain of function of the ataxin-3 protein, resulting in neuronal dysfunction and atrophy of specific brain regions over time. As ataxin-3 is a dispensable protein in rodents, ataxin-3 knockdown by gene therapy may be a powerful approach for the treatment of SCA3. In this study, we tested the feasibility of an adeno-associated viral (AAV) vector carrying a previously described artificial microRNA against in a striatal mouse model of SCA3. Striatal injection of the AAV resulted in good distribution throughout the striatum, with strong dose-dependent ataxin-3 knockdown. The hallmark intracellular ataxin-3 inclusions were almost completely alleviated by the microRNA-induced knockdown. In addition, the striatal lesion of dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) in the SCA3 mice was rescued by knockdown, indicating functional rescue of neuronal signaling and health upon AAV treatment. Together, these data suggest that microRNA-induced ataxin-3 knockdown is a promising therapeutic strategy in the treatment of SCA3.
脊髓小脑共济失调 3 型（SCA3）是一种由基因中 CAG 重复扩展引起的神经退行性疾病。这种突变导致ataxin-3 蛋白的毒性功能获得，导致神经元功能障碍和特定脑区的萎缩。由于 ataxin-3 在啮齿动物中是一种可有可无的蛋白质，因此通过基因治疗敲低 ataxin-3 可能是治疗 SCA3 的一种有效方法。在这项研究中，我们测试了携带先前描述的针对的腺相关病毒（AAV）载体在 SCA3 纹状体小鼠模型中的可行性。AAV 的纹状体注射导致其在纹状体中分布良好，具有强烈的剂量依赖性 ataxin-3 敲低。微 RNA 诱导的敲低几乎完全缓解了标志性的细胞内 ataxin-3 包涵体。此外，SCA3 小鼠中的多巴胺和 cAMP 调节神经元磷酸蛋白（DARPP-32）纹状体损伤通过敲低得到挽救，表明 AAV 治疗后神经元信号和健康得到了功能挽救。总之，这些数据表明，微 RNA 诱导的 ataxin-3 敲低是治疗 SCA3 的一种很有前途的治疗策略。
