HAIRPIN RIBOZYME GENE THERAPY FOR HCV INFECTION

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DESCRIPTION: (Adapted from the investigator's abstract) This Phase II SBIR proposal is aimed at the development of hairpin Ribozyme (RZ) gene therapy for the treatment of Hepatitis C virus (HCV) infection. HCV is the major cause of non-A, non-B hepatitis, which is a serious worldwide health problem, and ribozymes are RNA molecules that can be engineered to cleave and inactivate other RNA molecules in a sequence-specific fashion. The investigators believe that HCV is especially suited for ribozyme-mediated therapy, because the viral genome is present exclusively in the form of RNA and because HCV encodes only one primary transcript. Therefore, the applicants reason that cleavage of any target sequence within this RNA should abolish virus expression. Immusol has generated two hairpin ribozymes targeting the HCV positive strand RNA, and in the Phase I component of this project, additional Rz were identified targeting the negative strand, an even more attractive target due to its low expression level. In this Phase II proposal, the Principal Investigator proposes the optimization of the catalytic activity and stability of the top six Rz. Hepatocyte specific promoters will be used to express the Rz as single or polycistronic transcripts and the effectiveness of these multi-ribozyme vectors will be tested in a tissue culture reporter model. Development of an HCV replication system in liver cell culture is proposed, for final testing of the ribozyme vector before pre-clinical safety evaluation in a rat toxicity study. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE