Targeting Mutant Huntingtin Allele with WVE-120101: Selectivity and Brain Distribution Insights

The primary aim of the research was to explore the capacity of WVE-120101 to specifically target the mutated Huntingtin allele (mHTT) in vitro and to assess its distribution within non-human primates (NHPs). The study is grounded in the understanding that Huntington’s Disease (HD) arises from an expansion of CAG repeats in the HTT gene, and that the reduction of mHTT has been linked to symptom improvement or reversal. The challenge lies in developing drugs that can silence mHTT without affecting the normal HTT allele, as the latter could lead to adverse effects. Antisense oligonucleotides (ASOs), which are in various stages of clinical development for HD, are a complex group of molecules with different pharmacological impacts. WVE-120101 stands out as a stereopure ASO developed using a unique technology that provides a precise stereochemistry at each phosphorothioate (PS) linkage, which has been shown to enhance in vitro pharmacological properties such as activity, stability, and specificity.

The study's design included in vitro assessments of WVE-120101 and control ASOs' impact on RNase H activity, allele-specific mRNA expression, and comparative levels of mHTT and wtHTT protein expression in a reporter cell line and fibroblasts derived from patients. It also examined the distribution of WVE-120101 in the brains of NHPs following intrathecal administration.

The findings indicated that WVE-120101 selectively facilitated the RNase H cleavage of mHTT over wtHTT in vitro without triggering complement activation. It also selectively reduced levels of mHTT mRNA and protein in comparison to wtHTT across multiple cell lines. In NHPs, WVE-120101 was detected in the nuclear and perinuclear regions of neurons in brain regions implicated in HD pathology.

The conclusion drawn was that the stereopure ASO, WVE-120101, was able to selectively diminish mHTT in comparison to wtHTT and could reach brain regions implicated in HD. The study was supported by WAVE Life Sciences, with several researchers disclosing personal compensation for their association with the company. Dr. Davidson also reported receiving compensation from Spark Therapeutics, Inc., and research support from WAVE Life Sciences. Dr. Vargeese, on the other hand, was noted to have received personal compensation for his work with WAVE Life Sciences.