Figure 585

Possible mechanisms by which inserted therapeutic genes may alter cellular function. A. Gene addition with return to a normal phenotype. B. Dominant-negative or phenotype deletion. C. Gene addition to a unique phenotype, such as an enzyme that activates a prodrug.

ciency, which is an example of inherited SCID. ADA is a reasonable target for these reasons: (1) It is an autosomal recessive disorder in which a defect in a single gene produces absence of or diminished ADA activity with fatal combined immunodeficiency. (2) ADA expression is characteristic of a normal maintenance gene with considerable variation in the normal ADA levels, suggesting that stringent regulation of expression is unnecessary. (3) A significant level of expression is not required to correct the phenotype. (4) Ex vivo gene transfer studies can be conducted. (5) Replacement of ADA may reduce the production of toxic DNA metabolites and thus provide a growth advantage for transfected cells.

For ethical reasons, children enrolled in these clinical trials have also received standard therapy of enzyme infusions, so the results of these studies have been difficult to interpret and are controversial. Nevertheless, there is some evidence that the ex vivo gene transfer approach may evoke a biological response relevant to the treatment of ADA deficiency. Such interpretations have stimulated efforts to use the ex vivo strategy for other monogenic disorders, such as familial hypercholes-terolemia, hemophilia B, and Gaucher's disease.

Alternatively, the introduced gene could generate a protein that acts to block or suppress the function of another undesirable protein in a dominant-negative manner (Fig. 58.55). Last, the introduced gene could result in the production of an entirely new and unique protein that provides the recipient cell with a desirable pheno-type (Fig. 58.5C). In theory, an enzyme required for the metabolic activation of a prodrug could be expressed, leading to the desired pharmacological activity near the genetically altered cell. This approach is used in cancer gene therapy in which tumor cells are transfected with a gene encoding for an enzyme such as thymidine kinase in the presence of systemic administration of a nontoxic prodrug. The transfected enzyme in the tumor cells converts the prodrug, such as ganciclovir, to an active cytotoxic compound. Theoretically, such an approach selectively kills tumor cells and is nontoxic to untransfected cells. Clinical trials to assess the safety and efficacy of enzyme-prodrug cancer therapy are under way.

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