Chapter 9 - From huntingtin gene to Huntington’s disease-altering strategies

Abstract

In 1983, the huntingtin (HTT) gene was the first disease gene mapped to a specific chromosome. The precise nature of the Huntington’s disease (HD)-associated mutation was identified 10 years later as an expansion of CAG repeats in the HTT gene. Effective treatment for this devastating disease remains unavailable despite intensive efforts devoted to investigating the mechanisms of its pathogenesis and the identification of therapeutic candidates. The mutation in HD provides a strong and rational target for intervention, the HTT gene and its products. Approaches that target the polyglutamine-encoding mRNA/gene and block or reduce the production of HTT protein have the potential to delay disease progression and improve the quality of life of HD patients. The development of genome editing technologies may offer, for the first time, an opportunity to modify HTT expression, inactivate, or ultimately repair the mutant HTT gene. Accumulating preclinical data support clinical development of HTT-lowering strategies. They also highlight the advantages and limitations of these approaches. In this context, the first ASO-HTT clinical trial is an important step for the field and for the patients affected by this slowly progressing and fatal CNS disease.