Abstract
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.
Highlights
The term Spinocerebellar refers to the spinal cord and cerebellum, and ataxia means “absence of coordination”
This study showed that CYP46A1 expression is able to upregulate autophagy, which was shown to be dysfunctional in SCA3/MJD [43]
The results showed that human ataxin-1-like overexpression improved motor coordination in SCA1 mouse model and led to an improvement of neuronal function
Summary
The term Spinocerebellar refers to the spinal cord and cerebellum, and ataxia means “absence of coordination”. The firstbiased symptoms are usually gait ataxia, frequently soma mosaicism was reported as being the age of abnormalities onset and the followed by limb incoordination, speechassociated disturbance,with and oculomotor [14]severity according to the SCA subtype. Several of the gene therapies were developed toNortarget different pathways that are implicated in the disease pathogenesis In this line, themal strategies proposed ate for polyQ SCA treatment comprise the targeting of (i) mutant RNA, (ii) autophagy and SCA1. Other recent and advanced non-pharmaceutical strategies to PolyQ SCAs emerge from the use of different gene therapy strategies, namely gene augmentation, gene silencing, and gene editing These molecular therapies have the ability to delay the disease progression or potentially cure terminal or severely disabling conditions. As discussed in the future perspectives section, until now none of these strategies reached clinical trials and research must continue aiming to deliver one of these strategies to patients in the future
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