This paper examines gene therapy as a convergence of medicine, molecular biology, cell biology, and immunology. It surveys the evolution of genetic disease treatment — from early dietary and surgical interventions to modern gene transfer strategies — and outlines the range of viral and nonviral delivery vectors currently in use. The paper discusses key disease targets including Gaucher disease, cystic fibrosis, AIDS, cancer, and X-linked severe combined immunodeficiency (SCID-X1), and explains why different disorders require different therapeutic approaches. It also reviews the RNA/DNA hybrid oligonucleotide strategy for correcting single-nucleotide mutations and closes with a look at the future of vector development and human trials.
The treatment of genetic diseases has long appeared a daunting challenge because there seemed little to be done when the immutable basic blueprints of the body contain a serious imperfection (Beutler). Even fifty years ago, however, it was possible to greatly improve the quality of life and to actually save the lives of patients with some genetic diseases (Beutler). Successful approaches included dietary manipulation, as in phenylketonuria or galactosemia; surgery to correct various deformities; and avoidance of inciting environmental factors, as in acute intermittent porphyria (Beutler). Until the latter part of the twentieth century, however, the possibility of actually changing faulty genetic blueprints was beyond the imagination of the realistic medical scientist (Beutler).
Today it is certain that success in gene therapy will require the application of various techniques tailored to the disease being approached (Beutler). The majority of hereditary disorders will require approaches that result in prolonged expression of the transgene, although in some storage diseases — particularly Gaucher disease — transient expression may suffice to remove storage material that has accumulated over many years (Beutler).
Introducing a normally functioning gene will not be enough in some disorders, such as sickle cell disease; in those cases it will be necessary to block the function of the abnormal genes. In some acquired disorders, such as cancer, transient expression of a gene may be sufficient to obtain the desired clinical effect, while in others, such as rheumatoid arthritis, prolonged expression may be required (Beutler). The degree of control and the range of tissue expression will vary from application to application. Therefore, the design of appropriate gene therapy will require an understanding not only of the molecular biology of the gene being transferred, but also of the pathogenesis and clinical course of the disease being treated (Beutler).
Gene therapy is the fusion of medicine and a variety of scientific fields, including cell biology, molecular biology, and immunology, and is subject to the rigorous standards and guidelines of each of these fields (Beutler). Both viral and nonviral strategies for the delivery of exogenous genetic material to human cells have been developed (Beutler). Viral vectors include adenovirus, retrovirus, lentivirus, adeno-associated viruses, Semliki Forest virus, Sindbis virus, vaccinia virus, and SV40 (Beutler). Nonviral strategies utilize naked DNA, liposomes, proteins, and peptides, as well as other physical and chemical means (Beutler).
"Key diseases targeted by current gene therapy research"
"Molecular mechanism for correcting single-nucleotide mutations"
"Next steps in vector development and human trials"
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