Department of Neurology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Curr Opin Neurol. 2020 Aug;33(4):519-526. doi: 10.1097/WCO.0000000000000832.
Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is a fatal, dominantly inherited, neurodegenerative disease caused by expansion of a CAG repeat in the coding region of the ATXN3 gene. No disease-modifying treatment is yet available for MJD/SCA3. This review discusses recently developed therapeutic strategies that hold promise as future effective treatments for this incurable disease.
As a result of the exploration of multiple therapeutic approaches over the last decade, the MJD/SCA3 field is finally starting to see options for disease-modifying treatments for this disease come into view on the horizon. Recently developed strategies include DNA-targeted and RNA-targeted therapies, and approaches targeting protein quality control pathways and cellular homeostasis.
While still in preclinical testing stages, antisense oligonucleotides, short hairpin RNAs and citalopram all show promise to reaching testing in clinical trials for MJD/SCA3. Two pharmacological approaches in early stages of development, the slipped-CAG DNA binding compound naphthyridine-azaquinolone and autophagosome-tethering compounds, also show potential therapeutic capacity for MJD/SCA3. Overall, a handful of therapeutic options are currently showing potential as future successful treatments for fatal MJD/SCA3.
马查多-约瑟夫病（MJD），又称脊髓小脑共济失调 3 型（SCA3），是一种致命的、显性遗传的神经退行性疾病，由 ATXN3 基因编码区 CAG 重复扩展引起。目前尚无针对 MJD/SCA3 的治疗方法。本文综述了最近开发的治疗策略，这些策略有望成为治疗这种不治之症的有效方法。
由于过去十年中对多种治疗方法的探索，MJD/SCA3 领域终于开始看到针对这种疾病的治疗方法的选择。最近开发的策略包括 DNA 靶向和 RNA 靶向治疗，以及针对蛋白质质量控制途径和细胞内稳态的方法。
尽管仍处于临床前测试阶段，但反义寡核苷酸、短发夹 RNA 和西酞普兰都有望进入 MJD/SCA3 的临床试验测试。两种处于早期开发阶段的药理学方法，即 slipped-CAG DNA 结合化合物萘啶并氮杂喹啉和自噬体结合化合物，也显示出对 MJD/SCA3 的潜在治疗能力。总体而言，目前有几种治疗方法有潜力成为治疗致命的 MJD/SCA3 的有效方法。
