A decade after the initial use of viral-mediated gene transfer in human clinical trials, the hoped for goal of harnessing the vast information contained in our genes for effective therapy of a broad array of conditions has not yet been achieved. Especially for treatment of genetic diseases, progress using the general approach of “gene addition” has been agonizingly slow. This limited progress has been in part due to inefficient gene delivery, particularly for in vivo applications. Even in those systems where gene delivery is satisfactory, cell-to-cell variability in transgene expression as a result of random integration, the inability to reverse “dominant negative” gene disorders, and the lack of systems to provide normal “physiologic” regulation of the inserted transgene have kept most of the 3000+ monogenic disease targets off the lists of current candidate disorders. An alternative strategy for treatment of genetic diseases, gene repair has recently shown promise in both tissue culture and animal model studies. Chimeric oligonucleotides consisting of both DNA and RNA (chimeraplasts) are able to specifically and permanently change genomic DNA sequences. Using the cell's own DNA mismatch repair machinery, chimeraplasty has been shown to be active in bacteria, yeast, insects, plants, rodent, and human cells to either correct genetic defects or to disable normal gene functions. The properties of this gene repair system will be contrasted with technologies for gene addition as potential molecular tools for human therapy.
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