Current Status of Gene Therapy Research in Polyglutamine Spinocerebellar Ataxias

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.

RNA-based therapeutics for neurological diseases

“…The trinucleotide repeat disorders are also good candidates for AON targeting designed to downregulate toxic protein expression and reduce aggregation. In the case of SCA1, SCA2, SCA3 and SCA7 this has been investigated in mouse models where AONs delivered via intracerebroventricular injection reduced disease protein levels and improved phenotypes highlighting significant promise for AON therapy in this group of diseases [ 72–77 ]. For Huntington’s disease (HD), also a trinucleotide repeat disorder, multiple AONs designed to reduce the production of the huntingtin protein have been developed with promising results from early clinical trials [ 78–80 ].…”

“…siRNA also holds promise for the many genetic diseases discussed above for AON therapy. For example, there are numerous studies on the development of siRNA for the SCAs using various experimental systems, of which siRNA for SCA3/Machado-Joseph disease (MJD) has seen the most extensive effort towards allele-specific gene silencing [ 72 ]. Similarly, there is extensive siRNA-based research in the ophthalmology field with several ongoing clinical trials for disorders such as glaucoma, dry eye syndrome, age-related macular degeneration and diabetic macular oedema [ 37 ].…”

Polyglutamine Ataxias: Our Current Molecular Understanding and What the Future Holds for Antisense Therapies

“…The downregulation led to 14-week prevention of oligomeric and nuclear accumulation of ATXN3 and rescued the motor impairment attributed to defects in Purkinje neuron firing frequency. Several other studies using siRNA and RNAi have also shown a successful and sustained reduction in ATXN3, with a recent review of them and other gene therapy approaches found in [175].…”

“…Although siRNA-and RNAi-based therapeutics can be classified as antisense technologies, this review will only focus on splice switching and RNaseH mechanisms in relation to the causative genes of SCAs. Various RNA-silencing and gene-therapy approaches have been recently reviewed [175].…”

Mutant Ataxin-2 Expression in Aged Animals Aggravates Neuropathological Features Associated with Spinocerebellar Ataxia Type 2

“…The most common symptoms in SCA2 patients are motor ataxia and oculomotor dysfunction, with the slowing of saccades being a unique feature in SCA2 [ 6 ]. There is no cure for this disease [ 7 ].…”