Methods and compositions for treating Huntington's Disease

A method of reducing expression of a mutant Huntingtin (mHtt) gene to reduce or prevent the formation of Htt aggregates in a medium spiny neuron in a subject with Huntington's Disease (HD), the method comprising

• administering to the striatum of the subject a polynucleotide encoding a repressor of a mutant Htt (mHtt) allele, the repressor comprising a zinc finger protein designated 30640, 30645 or 33074, wherein the polynucleotide comprises an adeno-associated virus (AAV) vector administered at 2×1010 vector genomes, wherein the transcription factor repressor reduces mHtt expression by at least 85% in HD neurons in the striatum of the subject and reduces the formation of Htt aggregates in the medium spiny neuron by 20 to 50% as compared to an untreated subject.