ABSTRACT The cause of Huntington’s disease is an increase in the trinucleotide CAG repeat from under 36 repeats to 36 or greater repeats. The mode for the number of repeats is 42, and most patients have between 40 and 45. The disease generally starts between ages 30 and 40, with onset and progression of impaired cognition, depression, and aberrant movement. The genetics is autosomal dominant. Lowering mutant huntingtin in HD animal models delays onset of disease or mitigates the severity of disease. We use advanced, modified, di- branched siRNA to lower mutant huntingtin, by invoking RNA interference in brain. Our advanced siRNA achieves therapeutic advantages: spread throughout the brain in non- human primate and long-term huntingtin lowering after a single administration into the cerebrospinal fluid. The siRNA will be optimized in structure for safety and preliminary results will be secured. The goal of this CREATE proposal is to set the stage for promising therapeutics for treatment of Huntington’s disease. Similar treatments could be applicable to other autosomal dominant neurological disorders.