Development of Antisense Oligonucleotide 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 improve the pharmacokinetics and pharmacodynamics. In order to activate RNase H-mediated cleavage of the target mRNA, as well as to increase the binding affinity and specificity, gapmer AOs are designed to have a phosphorothioate (PS) backbone flanked with the modified AOs on both sides. Antisense-mediated knockdown of mutated huntingtin is a promising therapeutic approach for Huntington's disease (HD), a devastating disorder affecting the motor and cognitive abilities. This chapter focuses on the modified gapmer AOs for the treatment of HD.