Current Status of Gene Therapy Research in Polyglutamine Spinocerebellar Ataxias

• Published in: International journal of molecular sciences Vol. 22; no. 8; p. 4249
• Main Authors: Afonso-Reis, Ricardo, Afonso, Inês T, Nóbrega, Clévio
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19.04.2021; MDPI
• Subjects: Ataxia; Autophagy; Brain research; Cerebellum; Cholesterol; Degeneration; Disease; gene augmentation; gene editing; Gene silencing; Gene therapy; Genotype & phenotype; Health services; Homeostasis; Investigations; Neurodegeneration; Neuropathology; Pathogenesis; Polyglutamine; polyglutamine disorders; Proteins; Review; Spinocerebellar ataxia; Stem cells; Trinucleotide repeat diseases; Trinucleotide repeats; gene silencing; gene augmentation; gene therapy; gene editing; spinocerebellar ataxia; polyglutamine disorders
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22084249

Polyglutamine spinocerebellar ataxias (PolyQ SCAs) are a group of 6 rare autosomal dominant diseases, which arise from an abnormal CAG repeat expansion in the coding region of their causative gene. These neurodegenerative ataxic disorders are characterized by progressive cerebellar degeneration, which translates into progressive ataxia, the main clinical feature, often accompanied by oculomotor deficits and dysarthria. Currently, PolyQ SCAs treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression, which culminates with death. Over the last years, many promising gene therapy approaches were investigated in preclinical studies and could lead to a future treatment to stop or delay the disease development. Here, we summed up the most promising of these therapies, categorizing them in gene augmentation therapy, gene silencing strategies, and gene edition approaches. While several of the reviewed strategies are promising, there is still a gap from the preclinical results obtained and their translation to clinical studies. However, there is an increase in the number of approved gene therapies, as well as a constant development in their safety and efficacy profiles. Thus, it is expected that in a near future some of the promising strategies reviewed here could be tested in a clinical setting and if successful provide hope for SCAs patients.