Silencing Huntington’s Disease Gene with RNAi

Abstract

Huntington’s disease (HD), a hereditary condition afflicting 30,000 Americans, cannot be treated by existing therapies and it is universally fatal. It is characterized by movement disorder (Huntington’s chorea), emotional distress, and dementia. HD is caused by a highly penetrant, autosomal-dominant mutation in the HD gene at chromosomal locus 4p16.3. Expansion of the CAG repeat at the 5′-end of this gene increases the number of tandem glutamine residues in the encoded protein (huntingtin) from under 30 to 36–100 (or more). Most HD patients are heterozygotes, carrying one allele for the polyQ-expanded mutant huntingtin and one for the wild-type protein. The former protein is harmful, particularly to striatal neurons, whereas the latter is essential to neuronal survival. Experiments using RNAi are expanding our understanding of the functions of wild-type huntingtin. Using this technique, RNAi-based therapies for HD are being developed. Biotechnologies using both allele-specific and allele-nonspecific RNAi have proven effective at countering disease progression in multiple transgenic animal models for HD. RNAi against the transgene (mutant human HD transcript) decreases expression of the pathogenic protein and slows neurodegeneration. RNAi can be directed at a polymorphism linked to the polyQ-expansion mutation in HD. Consequently, the mutant allele is silenced while the wild-type one remains expressed. Such allele-specific silencing has been achieved in fibroblasts from HD patients. Technical improvements in local and systemic delivery combined with chemical modifications to the RNAi should improve efficiency and specificity thereby making RNAi-based therapy a successful treatment for HD.