Gene Therapy: Definition and Goals

GENE THERAPY: DEFINITION AND GOALS

The broadest definition of human gene therapy includes the in vivo (direct administration of the gene therapy formulation) and ex vivo (transfection of cells in tissue culture by gene therapy followed by administration of the transfected material into the patient) transfer of de-fined genetic material to cells of patients. Principles of gene therapy include transfer of one or more transgenes to prevent a disease, prevent an adverse consequence of a disease, or facilitate recovery from the consequence. Although most of the controversy and excitement have centered on the transfer of functional genes, the thera-peutic potential of genes that abrogate aberrant func-tion (e.g. antisense and ribonucleic acid–based strate-gies) should also be considered. 

Two fundamental ap-proaches underlie the basis of gene therapy. In the first, genetic material is introduced into cells to alter the cel-lular phenotype but not the genotype. This is typified by the transfer of unintegrated DNA, antisense oligomers, and ribozymes. In this regard, gene therapy has many ofthe attributes and problems of conventional endocrine or antimicrobial therapy with respect to efficiency of targeting and the duration of effect. A second approach seeks permanent alteration of the genotype of the cell, leading to a modified phenotype that prevents or alters a disease state. In this setting, gene therapy will perma-nently modify organ function.

Theoretically, mutated or nonfunctional genes could be excised and replaced, and new genes with desired functions could be permanently inserted into the genome. Stable integration of an antisense DNA might also be desirable in some circumstances. Because of the technical difficulties associated with the delivery of nu-cleic acid–based products selectively to specific target cells in vivo, more experimental information is available for ex vivo human gene therapy.