MOLECULAR THERAPY FOR RENAL DISEASES

The introduction of molecular therapy through the delivery of nucleic acids either as oligonucleotides or genetic constructs holds enormous promise for the treatment of renal disease. Significant barriers remai n, however, before successful organ-specific molecular therapy can be applied to the kidney. These include the development of methods to tar get the kidney selectively, the definition of vectors that transduce r enal tissue, the identification of appropriate molecular targets, the development of constructs that are regulated and expressed for long pe riods of time, the demonstration of efficacy in vivo, and the demonstr ation of safety in humans. As the genetic and pathophysiologic basis o f renal disease is clarified, obvious targets for therapy will be defi ned, for example, polycystin in polycystic kidney disease, human immun odeficiency virus (HIV) type 1 in HIV-associated nephropathy, cu-galac tosidase A in Fabry's disease, insulin in diabetic nephropathy, and th e ''minor'' collagen IV chains in Alport's syndrome. In addition, seve ral potential mediators of progressive renal disease may be amenable t o molecular therapeutic strategies, such as interleukin-6, basic fibro blast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-beta). To test the in vivo effic acy of molecular therapy, appropriate animal models for these disease states must be developed, an area that has received too little attenti on. For the successful delivery of genetic constructs to the kidney, b oth viral and nonviral vector systems will be required. The kidney has a major advantage over other solid organs since it is accessible by m any routes, including intrarenal artery infusion, retrograde delivery through the uroexcretory pathways, and ex vivo during transplantation. To further restrict expression to the kidney, tropic vectors and tiss ue-specific promoters also must be developed. For the purpose of inhib ition of endogenous or exogenous genes, current therapeutic modalities include the delivery of antisense oligodeoxynucleotides or ribozymes. For these approaches to succeed, we must gain a much better understan ding of the nature of their transport into the kidney, requirements fo r specificity, and in vivo mechanisms of action. The danger of a rush to clinical application is that superficial approaches to these issues will likely fail and enthusiasm will be lost for an area that should be one of the most exciting developments in therapeutics in the next d ecade. (C) 1996 by the National Kidney Foundation, Inc.