Gene therapy: mechanisms, applications, and clinical developments

Gene Therapy

The treatment of genetic diseases has appeared a daunting challenge because there seemed little to be done if the immutable basic blueprints of the body have a serious imperfection (Beutler Pp). Even fifty years ago it was possible to greatly improve the quality of life and to actually "save the lives of patients with some such genetic diseases" (Beutler Pp). Success approaches included dietary manipulation as in phenylketonuria or galactosemia, surgery to correct various deformities, and often avoidance of inciting factors in the environment, "as in acute intermittent porphyria" (Beutler Pp). However, until the latter part of the twentieth century, the possibility of actually changing the faulty genetic blueprints was beyond the imagination of the realistic medical scientist (Beutler Pp).

Today it is certain that success in gene therapy will require the application of various technique that are tailored to the disease that is being approached (Beutler Pp). The majority of hereditary disorders will require approaches that "result in prolonged expression of the transgene, although in some storage diseases, particularly Gancher disease, transient expression may suffice to remove storage material that has accumulated over many years" (Beutler Pp).

Introducing a normally functioning gene will not be enough in some disorders such as sickle cell disease, and it will necessary to block the function of the abnormal genes, and 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 Pp). The degree of control and the range of tissue expression will vary from application to application, thus, the design of appropriate gene therapy will require understanding not only of the molecular biology of the gene that is being transferred, but of the pathogenesis and clinical course of the disease that is being treated as well (Beutler Pp).

Gene therapy is the fusion of medicine and a variety of scientific fields, including cell biology, molecular biology, and immunology and is subject to all the rigorous standards and guidelines of each of these fields (Beutler Pp). Both viral and nonviral strategies for the delivery of exogenous genetic material to human cells have been developed (Beutler Pp). The viruses include "adenovirus, retrovirus, lentivirus, adeno-associated viruses, Semliki Forest virus, Sindbis virus, vaccinia virus, and SV40" (Beutler Pp). Nonviral strategies utilize naked DNA, liposomes, proteins, and peptides, as well as other physical and chemical means (Beutler Pp).

"Targets of gene therapy for human disease include Gaucher disease, adenosine deaminase deficiency,

X-linked severe combined immunodeficiency

(SCID-X1), cystic fibrosis, cancer, acquired immunodeficiency syndrome (AIDS), cardiovascular disease, and rheumatoid arthritis" (Beutler Pp).

In the case of X-linked severe combined immunodeficiency, gene therapy has succeeded in correcting the disease (Beutler Pp).