RNAi Approaches

RNA interference is a gene-silencing process that uses short interfering RNA (siRNA), short hairpin RNA (shRNA), bi-functional shRNA and microRNA (miRNA). The combination of neural progenitor stem cell therapy and RNAi therapy can ameliorate symptoms in mouse models of HD [118]. In the animal models (R6/1, R62, N171-82Q, RAT AAV-HD70d) of HD, siRNA, shRNA, and miRNA treatments have been used to reduce neuropathology and improve motor function [6,72,104]. AMT-130 (adeno-associated virus vector) contains an artificial miRNA which produces a huntingtin-lowering molecule. Side e ffects include peripheral neuropathy observed in clinical trials of siRNA. RNAi has been tested in rodents and its delivery system has been tested in nonhuman primates [119].

#### Small Molecule Approach

Small molecules like RG7800 showed ocular complications in the Δ7 mouse model of spinal muscular atrophy (SMA) [120], while the phase I trial of the molecule RG7916 (risdiplam) was recently completed (NCT02633709). RG7800 and RG7916 are splicing modifiers, which change the way the pre-mRNA is spliced so that it contains all the information necessary to make a functional protein. They promote the production of a full-length and functional protein from the gene. RG7800 increases the survival motor neuron (SMN) protein level by modifying the splicing of the SMN2 mRNA. RG7800 is shown to promote the inclusion of exon 7 in SMN2 mRNA, generating full-length mRNA, using fibroblasts from an SMA type I patient. In the SMA mouse model, the treatment of RG7800 showed a dose-dependent increase in SMN protein levels [121]. Oral administration of RG7800 in SMA patients increased the functional SMN protein level up to two-fold from baseline [122]. New work is now underway to identify these molecules and their possible role in the lowering of mutant *HTT* gene and protein expression [102,123].

#### *3.8. Other Therapeutics Advancements*
