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Chapter: Modern Pharmacology with Clinical Applications: Gene Therapy

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Disease Application and Future Directions

A proportion of the human gene therapy trials ap-proved by the OBA seek to correct a single-gene de-fect, such as adenosine deaminase deficiency, gluco-cerebrosidase deficiency in Gaucher’s disease, or the mutated chloride transport gene in cystic fibrosis.

DISEASE APPLICATION AND FUTURE DIRECTIONS

 

Antisense clinical trials, most with phosphorothioates, have been directed toward blocking viral production in patients with AIDS or genital warts, disrupting the functionality of protooncogenes in cancer, blocking immune cell activity after kidney transplantation, treating rheu-matoid arthritis, or influencing autoimmune diseases. Studies to date have not reported marked clinical effi-cacy, which might be due to protein binding and poor entry into cells. Additional chemical modifications and possibly the use of carriers, such as liposomes, may im-prove drug delivery and utility.

 

A proportion of the human gene therapy trials ap-proved by the OBA seek to correct a single-gene de-fect, such as adenosine deaminase deficiency, gluco-cerebrosidase deficiency in Gaucher’s disease, or the mutated chloride transport gene in cystic fibrosis. The major difficulties limiting success have been immuno-genicity associated with the vector delivery system, low transfection efficiency, and transient transgene ex-pression.

 

Most human gene therapy trials are designed to ex-press a new gene product that facilitates the correction of a disease process, such as cancer. Almost half of the cur-rent gene therapy–based protocols in the United States are aimed at boosting the immune response to tumor antigens. Thus, there are attempts to express the lym-phokine interleukin-2 in tumor cells to stimulate a nat-ural immune response against the producing tumor cell and its malignant neighbors. In other types of studies, malignant cells infected with a vector that encodes a tu-mor suppressor gene, p53, lead to growth arrest, apo-ptosis or enhanced sensitivity to cytotoxic agents. Others have used vectors encoding the herpesvirus pro-tein thymidine kinase that target cells for killing when exposed to the antiviral prodrug ganciclovir; this is known as suicide gene therapy. Similarly, attempts are being made to produce HIV-infected cells that express thymidine kinase or other enzymes that activate the nontoxic prodrugs to cytotoxic compounds. Disruption of viral functions with decoy molecules that compete with, sequester, or cleave products produced by HIV also is being examined.

 

Most of these trials have been early phase I or II studies that are designed to evaluate safety rather than efficacy of the gene therapy formulation. Results of ongoing and pending phase III studies will more precisely place the role of gene therapy in a clinical context. Although the feasibility of human gene trans-fer has been demonstrated in the completed clinical trials, there has been a paucity of evidence to support the efficacy and reliability of gene transfer ap-proaches. Future gene therapy studies will capitalize on preclinical efforts to improve cellular targeting, gene transfer efficiency, and sustained expression. Regulation of the expression of the introduced trans-gene would be desirable, and use of cell type–specific promoters, such as the actin or surfactant promoter, or drug-controlled promoters, such as the tetracy-cline promoter, are being examined in preclinical models.

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