Summary

The types of disorders considered as potential targets for gene therapy has changed with the development of the field. Initially, most studies centered on developing therapies for single gene defect disorders; however, these present the greatest challenges. Thus, increasingly more attention is being paid to complex diseases involving more than 1 gene, such as cardiovascular disease and cancer, because these appear more tractable. In addition, although efforts attempting to correct genes

Figure 10 Tet-regulated expression of two separate genes. By coexpressing two tetR-based activators that contain DNA-binding domains with distinct specificity, respond oppositely to dox, and do not heterodimerize, two independent genes can be regulated by the same inducer. Because of the characteristic dose response of the wild-type and ''reverse'' tetR, the expression of each gene can be turned off at an intermediate concentration of dox and activated at markedly different dox concentrations. (Reprinted from Ref. 138 with permission of the Proceedings of the National Academy of Sciences USA, 2101 Constitution Ave., NW, Washington, DC 20418. Reproduced by permission of the publisher via Copyright Clearance Center, Inc.)

Figure 10 Tet-regulated expression of two separate genes. By coexpressing two tetR-based activators that contain DNA-binding domains with distinct specificity, respond oppositely to dox, and do not heterodimerize, two independent genes can be regulated by the same inducer. Because of the characteristic dose response of the wild-type and ''reverse'' tetR, the expression of each gene can be turned off at an intermediate concentration of dox and activated at markedly different dox concentrations. (Reprinted from Ref. 138 with permission of the Proceedings of the National Academy of Sciences USA, 2101 Constitution Ave., NW, Washington, DC 20418. Reproduced by permission of the publisher via Copyright Clearance Center, Inc.)

that are defective are under development, currently methods for complementing their defects through recombinant expression of related genes are more readily achieved. As the strategies for gene therapy develop in complexity, the methods available for treatment of disorders must also increase in their level of sophistication. Because of its many advantages, my-oblast-mediated gene delivery may be a method well suited for addressing these needs for certain types of diseases. My-

oblasts can be multiply transduced ex vivo with a variety of retroviral cassettes, each containing separate genes. The availability of improved tet-inducible retroviral vectors allows for fine control of recombinant gene expression levels. The 2 systems together—ex vivo gene transfer using myoblasts and regulatable retroviral vectors for transducing my-oblasts—contribute a powerful toolbox with which to develop gene therapies for a number of human diseases. If myogenic stem cells prove to be readily isolated, cultivated, and able to migrate to muscle tissue, a large percentage of muscle could be targeted with relative ease, allowing for broad application in the treatment of both inherited myopathies and nonmuscle-related disorders.

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