Renal disease is an increasingly major health problem with a growing number of patients requiring dialysis each year. Multiple factors appear to contribute to the development of renal diseases including viral and bacterial infections, tissue injury, as well as genetic and environmental factors. Renal injury induced by viral infection (i.e., HIV) may result from the effects of viral polypeptides directly on the kidney or alternatively, through perturbations of cytokine gene expression. The role of host factors is particularly emphasized by the demographics of HIV associated nephropathy, where the disease is found almost exclusively among African Americans and Hispanics. Studies using an HIV transgenic mouse model with a similar renal disease phenotype suggest elevated levels of transforming growth factor-beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF) may be contributing factors in pathogenesis. These cytokines have also been implicated in other experimental models for renal disease and in man. For the effective treatment of HIV nephropathy it may be important to regulate viral gene expression and cytokine gene expression in the kidney. Toward this end we propose to utilize targeted ribozymes as therapeutic agents for the treatment of renal diseases. Ribozymes are RNA molecules derived from plant viroids which can cleave mRNA. The """"""""hammerhead and hairpin"""""""", two ribozyme prototypes which have been applied to gene therapeutic strategies can be adapted to cleave target mRNAs. We have demonstrated the in vitro efficacy of an HIV targeted ribozyme. We propose the development of additional ribozymes to cleave TGF-beta1, and bFGF. Cell culture and in vivo studies will be performed to assess the efficacy of targeted ribozymes. Successful gene therapy strategies for renal disease will require delivery systems with cell-type specificity of expression. Since few promoters have been identified with defined renal cell-type specificity, an additional aim of this proposal is to identify renal cell-type specific genes and their cognate promoters. These promoters, in combination with targeted ribozymes, may provide useful therapeutic strategies for the treatment of renal diseases.
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