Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

Abstract

Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs have progressive ataxia as their main clinical feature, frequently accompanied by dysarthria and oculomotor deficits. The most common spinocerebellar ataxias (SCAs) are 6 polyglutamine (polyQ) SCAs. These diseases are all caused by a CAG repeat expansion in the coding region of a gene. Currently, no curative treatment is available for any of the polyQ SCAs, but increasing knowledge on the genetics and the pathological mechanisms of these polyQ SCAs has provided promising therapeutic targets to potentially slow disease progression. Potential treatments can be divided into pharmacological and gene therapies that target the toxic downstream effects, gene therapies that target the polyQ SCA genes, and stem cell replacement therapies. Here, we will provide a review on the genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias.

Keywords: SCA; Spinocerebellar ataxia; antisense oligonucleotides; gene therapy; polyglutamine disorders; stem cell-based therapy.

Fig. 1

Worldwide prevalence of polyglutamine spinocerebellar ataxias. In the ADCA families investigated, no SCA17 was identified. The Netherlands [8]; Germany [9]; Japan [10]; the USA [11]; Portugal/Brazil [12]; Italy [13]; China [14]; South Africa [15]; India [16]. Figure based on Schols et al. [17] and adapted from Bird [18] (GeneReviews)

Fig. 2

Potential genetic therapies for the polyQ SCAs. Several different nucleic acid-based molecules (top panel) are available to target the RNA or DNA of the polyQ-associated genes. The different therapeutic molecules differ in their chemical composition, delivery method, and functional mechanism. AONs can be delivered to the central nervous system as naked molecules, since their distribution, uptake, and stability in this context are excellent. CRISPR/Cas and double-stranded RNA molecules require supportive delivery methods, such as viral vectors or lipid nanoparticles. Assisted delivery of these types of molecules can be performed using different viruses, where nonintegrative gene therapy vectors based on AAV are usually preferred to avoid random integration and mutagenesis. AONs can be used to induce mRNA degradation (gapmer AONs), which activate RNase H due to formation of an RNA–DNA hybrid. Alternatively, fully 2′O-modified AONs do not activate RNase H and can be implemented to affect splicing and remove the CAG-containing exon. Downregulation of target transcripts can also be achieved through miRNA, shRNA, or siRNA. miRNA is generally designed with a mismatch, resulting in translational inhibition. shRNA and siRNA act through the same RISC pathway to degrade target mRNA. CRISPR/Cas is the most recent genetic therapy and the only strategy listed here that is able to target DNA. It can be used to inhibit expression by introducing insertions/deletions through nonhomologous end joining (NHEJ) or can introduce a corrected DNA sequence through homology-directed repair (HDR). In principle, all the mentioned molecules can be used to target SNPs associated with the pathogenic allele, resulting in downregulation or correction of the mutant allele. AON = antisense oligonucleotide, CRISPR/Cas = clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease, dsRNA = double-stranded RNA, gRNA = guide RNA, HDR = homology-directed repair, miRNA = microRNA, mRNA = messenger RNA, NHEJ = nonhomologous end joining, RISC = RNA-induced silencing complex, shRNA = short hairpin RNA, siRNA = small interfering RNA, SNP = single nucleotide polymorphism