Table 3.
Gene therapies
| SCA | Mechanism | Model system | Outcome | Reference |
|---|---|---|---|---|
| SCA1 | miRNA: miR-19, miR-101, and miR-130 | MCF7 and HEK293T cells | ± 60% reduction of ataxin-1 protein | [189] |
| SCA1 | miRNA: miR-144 and miR-101 | HEK293T cells | 20–30% reduction of ataxin-1 protein | [190] |
| SCA3 | miRNA: ban miRNA | Drosophila | Suppression of neurodegeneration | [191] |
| SCA3 | miRNA: miR-34 | Drosophila | Reduced inclusion formation; the protein retained greater solubility, and neural degeneration was suppressed | [192] |
| SCA3 | miRNA: mir-9, mir-181a, and mir-494 | SCA3 mice | Reduction of ATXN3 levels, aggregate counts, and neuronal dysfunction | [193] |
| SCA6 | miRNA: miR-3191-5p | SCA6 KI mice | Alleviation of motor deficits and Purkinje cell degeneration | [194] |
| SCA7 | miRNA: miR-124 | N2A cells and SCA7 mice | ± 80% reduction of ataxin-7 | [195] |
| SCA1 | shRNA: ataxin-1 downregulation | SCA1 mice | No efficiency data on RNA or protein level; improved motor coordination, restored cerebellar morphology, and resolved characteristic ataxin-1 inclusions in Purkinje cells | [196] |
| SCA1 | Artificial miRNA harboring a siRNA | SCA1 KI mice | 58–72% reduction of both ATXN1 and Atxn1; improvement of rotarod performance and neuropathology | [197, 198] |
| SCA1 | Artificial miRNA harboring a siRNA | B05 transgenic SCA1 mice | Improved behavior paradigms and neuropathology | [198, 199] |
| SCA1 | Artificial miRNA harboring a siRNA | Rhesus monkeys | ≥ 30% reduction of ATXN1 mRNA levels | [200] |
| SCA3 | Artificial miRNA harboring a siRNA | HEK293 cells and MJD84.2 SCA3 mice | ± 75% reduction of ataxin-3 levels (in vitro and in vivo); alleviation of nuclear accumulation of mutant ataxin-3 | [201] |
| SCA3 | Artificial miRNA harboring a siRNA | MJD84.2 SCA3 mice | Lifelong suppression of ATXN3 in the cerebellum; no mitigation of motor impairment and prolonged survival | [202] |
| SCA3 | siRNA | SCA3 mice | Reduction of both behavior deficits and neuropathology | [203] |
| SCA7 | Artificial miRNA harboring a siRNA | SCA7 mice | ≥ 50% reduction of mutant and wild-type ataxin-7 | [204] |
| SCA7 | Artificial miRNA harboring a siRNA | SCA7 mice | Improvement of ataxia phenotypes and a reduction in cerebellar molecular layer thickness and nuclear inclusions | [205] |
| SCA3 | siRNA: allele-specific downregulation | COS-7 and HeLa cells | > 90% reduction of mutant ataxin-3 and 25% reduction of WT ataxin-3 | [206] |
| SCA3 | siRNA: allele-specific downregulation | HEK293T cells | 96% reduction of mutant ataxin-3 and 6% reduction of WT ataxin-3 | [207] |
| SCA6 | siRNA: allele-specific downregulation | HEK293T cells | > 90% reduction of the mutant protein and no reduction of WT levels | [208] |
| SCA7 | siRNA: allele-specific downregulation | SCA7 patient-derived fibroblasts | More efficiently silencing of mutant transcript, but allele selectivity is lost at the highest dose of siRNA | [209] |
| SCA3 | shRNA: allele-specific downregulation | SCA3 rat model | Mitigated neuropathological abnormalities | [210] |
| SCA3 | shRNA: allele-specific downregulation | SCA3 mice | Alleviation of motor and neuropathological phenotypes | [211, 212] |
| SCA3 | AON: ataxin-3 downregulation | MJD84.2 SCA3 mice | 30% reduction mutant ataxin-3; over 75% reduction in ataxin-3 oligomers; strong improvement of motor phenotype | [213, 214] |
| SCA3 | AON: allele-specific downregulation by targeting CAG repeat | SCA3 fibroblasts | Complete downregulation of ataxin-3 protein, with preferential targeting of mutant protein | [215, 216] |
| SCA3 | AON and ss-siRNA: allele-specific downregulation by targeting CAG repeat | SCA3 fibroblasts | Complete downregulation of ataxin-3 protein, preferential targeting of mutant protein | [217] |
|
SCA1 SCA3 |
AON: allele-specific downregulation by targeting CAG repeat | Fibroblasts | Reduction of ATXN1 and ATXN3 mutant allele at RNA; other ataxin RNAs not tested | [218] |
| SCA2 | AON: ataxin-2 downregulation | ATXN2-Q127 and BAC-Q72 SCA2 mice | Up to 75% reduction of ataxin-2 protein in Purkinje cells of the mouse brain and significant improvement of motor phenotype | [219] |
| SCA7 | AON: allele-specific ataxin-7 downregulation | SCA7 fibroblasts | Mutant ataxin-7 reduced up to 50% and UCHL1 expression restored | [220] |
| SCA3 | CRISPR/Cas9 | Neurons derived from patient-specific iPSCs | Successful removal of polyQ-encoding region; the ubiquitin-binding capacity of ATXN3 was retained | [221] |
HEK = human embryonic kidney; MCF7 = Michigan Cancer Foundation-7; COS-7 = CV-1 in Origin Simian-7; miRNA = microRNA; siRNA = small interfering RNA; shRNA = short hairpin RNA; AON = antisense oligonucleotide