Prion diseases are invariably fatal infectious diseases of the central nervous system. The prion protein has been identified as the underlying causative agent as PrP knockout mice (prnp(0/0)) are resistant to infection. This suggests that a significant reduction in the expression levels of PrP(c) should interrupt disease progression. Accomplishing this in vivo, upon presentation of symptoms, requires a mechanism that significantly reduces prnp mRNA levels while lacking potential side effects that may be cytotoxic or lethal to the host. Hybrid hammerhead ribozymes (HyHamRzs) include both a helicase recruitment signal and a tRNA(Val) promoter. HyHamRzs offer a means of highly specific and significant mRNA cleavage. In this study, data demonstrate increased activity granted to HamRzs by the addition of the helicase recruitment signal. Results show that three different HyHamRzs, targeting different locations along the full length prnp mRNA, reduced expression levels by greater than 95% relative to the control. It is postulated that HyHamRzs, modified to enhance serum stability and delivered intravenously to neurons by forming a complex with the modified rabies virus G protein (RVG), may offer a potential gene therapy strategy.