To our knowledge, this is the first study to investigate the potential of system-delivered, vectorized CAG-targeted shReagents as a therapy in HD and SCA3 using humanized animal models that harbor human normal and mutant huntingtin protein (HTT) and similarly for human ataxin-3 protein (ATXN3). The gene discussed is HTT; the disease is Spinocerebellar ataxia type 3.