MOLECULAR THERAPY FOR RENAL DISEASE

Mount Sinai School Of Medicine Of Nyu, New York NY

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Linked publications & trials

Abstract

This Program Project will address in a coordinated fashion several of the key questions that must be answered before molecular therapy (systemic antisense and gene therapy) can be successfully introduced to patients for the treatment of renal diseases. These include: What are appropriate molecular targets? What are effective approaches to inhibit gene expression? Can vectors be targeted to renal tissue? Can long-term benefits be achieved? In addressing these questions, we will utilize a multidisciplinary approach to accomplish the following specific aims: 1: To determine the molecular basis of antisense DNA uptake into kidney, to clone and characterize a channel that conducts DNA into renal cells; to determine whether this form of therapy can be modified to enhance or reduce delivery to kidney, and to determine whether therapy can ameliorate renal disease in vivo. 2: To develop ribozymes directed to likely renal targets such as TGFbeta1, bFGF, and HIV-1, to maximize their enzymatic cleavage kinetics, and to assess in vivo efficacy and toxicity. 2/3: To utilize constitutive promoters to direct ribozyme therapy initially and then to define renal-specific and segment-specific promoters that can be used for gene therapy constructs for the treatment of renal diseases in the future. 3: To develop viral (adeno-associated virus) and non-viral (liposome) vectors for gene delivery, to test the efficiency and specificity of delivering exogenous genes to specific cell types within the kidney (mesangial and epithelial) using these vectors, to determine the efficiency, distribution and duration of expression of exogenous genes in kidney, and to optimize vectors for the successful delivery of ribozymes and/or antisense in vivo using small animal models. Efficiency of gene delivery, extent of cellular transduction, site of integration, and duration of expression will be explored using indicator and therapeutic constructs. Once antisense and ribozyme therapies have been optimized and the delivery systems characterized, efficacy and toxicity will be addressed using transgenic technology. For therapeutic benefit, promising constructs will be tested in an animal model in which renal expression of a foreign gene induces progressive renal insufficiency. The results from this program project should assist the renal community by providing the needed information to facilitate the movement of molecular therapies to patients with diseases of the kidney.