Antisense Oligonucleotide Therapy: From Design to the Huntington Disease Clinic

Huntington disease (HD) is a fatal progressive neurodegenerative disorder caused by an inherited mutation in the huntingtin (HTT) gene, which encodes mutant HTT protein. Though HD remains incurable, various preclinical studies have reported a favorable response to HTT suppression, emphasizing HTT lowering strategies as prospective disease-modifying treatments. Antisense oligonucleotides (ASOs) lower HTT by targeting transcripts and are well suited for treating neurodegenerative disorders as they distribute broadly throughout the central nervous system (CNS) and are freely taken up by neurons, glia, and ependymal cells. With the FDA approval of an ASO therapy for another disease of the CNS, spinal muscular atrophy, ASOs have become a particularly attractive therapeutic option for HD. However, two types of ASOs were recently assessed in human clinical trials for the treatment of HD, and both were halted early. In this review, we will explore the differences in chemistry, targeting, and specificity of these HTT ASOs as well as preliminary clinical findings and potential reasons for and implications of these halted trials.

Automated summary

Huntington disease is a fatal neurodegenerative disorder caused by an inherited mutation in the huntingtin gene. Lowering mutant huntingtin protein (HTT) has shown promise as a potential disease-modifying treatment. Antisense oligonucleotides (ASOs) that target HTT transcripts offer a suitable approach, and they have gained attention as a therapeutic option for Huntington disease. However, recent clinical trials assessing two types of ASOs for Huntington disease were halted early.