Sequence-specific cleavage of Huntingtin mRNA by catalytic DNA

The selective loss of neurons in Huntington's disease (HD) is caused by the abnormal expansion of the CAG triplet (>36 repeats) of the HD gene. Althou gh the molecular events that lead to neuronal death are not clear, it is mo st likely that mutant HD protein operates through a "gain-of-function" mech anism. One possible therapeutic approach that does not require definition o f the toxic mechanism(s) involves reduction in the levels of mutant HD prot ein by decreasing the quantity of translatable HD mRNA. In this report, we demonstrate the first effective destruction of the HE mRNA, using a catalyt ic DNA-an oligodeoxynucleotide with RNA-cleaving enzymatic activity. We sho w that the cleavage of HD mRNA by the catalytic DNA occurs in a sequence-sp ecific manner, and leads to significant reduction of HD protein expression in mammalian cells. The catalytic DNAs we have developed are a valuable res earch tool for studying HD, and may have the therapeutic potential of reduc ing cellular toxicity caused by mutant I-ID protein.