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Gene Repair and Transposon-Mediated Gene Therapy

^a Department of Medicine,
^b Department of Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, Minnesota, USA;
^c Institute of Liver Studies, Kings College Hospital, Denmark Hill, London, England

Key Words. Chimeraplasty • Gene repair • Chimeric RNA/DNA oligonucleotide • Single-stranded oligonucleotide • Triplex-forming oligonucleotide • Small fragment homologous replacement • Sleeping Beauty transposon system

Correspondence: Clifford J. Steer, M.D., Department of Medicine, Mayo Mail Code 36, Mayo Building, Room A536, 420 Delaware Street S.E., Minneapolis, Minnesota 55455, USA. Telephone: 612-624-6648; Fax: 612-625-5620; e-mail: steer001{at}tc.umn.edu

The main strategy of gene therapy has traditionally been focused on gene augmentation. This approach typically involves the introduction of an expression system designed to express a specific protein in the transfected cell. Both the basic and clinical sciences have generated enough information to suggest that gene therapy would eventually alter the fundamental practice of modern medicine. However, despite progress in the field, widespread clinical applications and success have not been achieved. The myriad deficiencies associated with gene augmentation have resulted in the development of alternative approaches to treat inherited and acquired genetic disorders. One, derived primarily from the pioneering work of homologous recombination, is gene repair. Simply stated, the process involves targeting the mutation in situ for gene correction and a return to normal gene function.

Site-specific genetic repair has many advantages over augmentation although it too is associated with significant limitations. This review outlines the advantages and disadvantages of gene correction. In particular, we discuss technologies based on chimeric RNA/DNA oligonucleotides, single-stranded and triplex-forming oligonucleotides, and small fragment homologous replacement. While each of these approaches is different, they all share a number of common characteristics, including the need for efficient delivery of nucleic acids to the nucleus. In addition, we review the potential application of a novel and exciting nonviral gene augmentation strategy—the Sleeping Beauty transposon system.

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