Development of Antisense Gapmers for the Treatment of Huntington's Disease.

The field of neuromuscular and neurodegenerative diseases has been revolutionized by the advent of genetics and molecular biology to evaluate the pathogenicity, thereby providing considerable insight to develop suitable therapies. With the successful translation of antisense oligonucleotides (AOs) from in vitro into animal models and clinical practice, modifications are being continuously made to the AOs to enhance their pharmacokinetics and pharmacodynamics. In order to activate RNase H1-mediated cleavage of the target mRNA, as well as to increase the binding affinity and specificity, gapmer AOs are designed with a central DNA gap, often with a phosphorothioate (PS) backbone, flanked with the modified AOs on both sides that improve stability and binding affinity. Antisense-mediated knockdown of mutated huntingtin is a promising therapeutic approach for Huntington's disease (HD), a devastating disorder affecting motor and cognitive abilities. This chapter focuses on the modified gapmer AOs for the treatment of HD.