ASO Approaches

ASO are single-stranded DNA (ssDNA) molecules that primarily bind to a specific sequence on RNA and regulate post-transcriptional gene expression [112]. The ssDNA di ffuses well in the CNS and is taken up by neurons. Therefore, the injection of ASOs into the cerebrospinal fluid (CSF) results in ubiquitous delivery of drugs and suppresses the production of mHTT [70] (Table 1). However, ASO delivery has some side e ffects, like thrombocytopenia which was observed in some human trials of ASOs [113]. ASO can ameliorate transcriptional dysregulation and reduce the level of mHTT and improve behavior in the YAC128, YAC18, and BACHD mouse models of HD [114,115].

IONIS-HTTRx is an important ASO. It has 12–25 nucleotides and transforms phosphodiester linkages to phosphorothioate. IONIS-HTTRx caused a remarkable reduction in *HTT* mRNA and protein expression [71]. The injection of ASOs (conjugated with peptides), produced wide CNS distribution and longer life span in the spinal muscular atrophy (SMA) mouse model [116]. In a recent study of phase I–IIa trial, HTTRx lessened the concentration of mutant *HTT* in CSF of HD patients. Therefore, ASO compounds not only suppress the expression of *HTT* mRNA and the huntingtin protein in CNS, but also in CSF [117].
