Prospects for Human Gene Therapy

Abstract

The introduction of the adenosine deaminase (ADA) gene into mature lymphocytes of a patient with ADA deficiency offers only a temporary treatment of the immunodeficiency but has paved the way for potential cure of this and other inherited diseases through the use of somatic gene therapy. Rapid progress in the development of molecular technology has resulted in the identification of a number of disease genes, the subsequent cloning of their normal counterparts, and has enabled scientists to address correction of these inherited disorders. Large amounts of gene products can now be produced by recombinant technology and initial therapeutic efforts focused on the in vivo administration of such purified recombinant proteins. This therapeutic approach has been ineffective in the treatment of genetic diseases in which the activity of the enzyme is located within the cell, with the notable exceptions of ADA deficiency and Gaucher disease (1). Even when addition of the deficient enzyme has been found to correct the biochemical defect in vitro, in vivo administration of the enzyme has generally not proven to be adequate therapy for correction of the defect due to either accelerated metabolism of the protein or an enhanced immune response to the protein. Research efforts in the correction of inherited defects have thus been directed to the transfer of normal genes to autologous target cells and the reintroduction of these cells into the patient. The use of various strategies to transfer genetic sequences into somatic cells from patients and their readministration to the patient for clinical benefits constitutes somatic gene therapy (2). The requirements for a successful gene therapy protocol include: (i) identification and availability of the defective gene (cloned) (ii) knowledge of the biology and regulation of the gene in the target tissue and (iii) the ability to transduce sufficient numbers of target cells as well as ensuring proper gene regulation. Although most commonly considered in the context of inherited single gene defects because of the extensive molecular knowledge of the defective gene and target cell involved, gene therapy plays an increasingly greater role in the therapy of acquired diseases, as the genes and target cells involved in these disorders are identified and new methods of gene transfer are developed.