Gene Therapy

The revolution in molecular biology, based on recombinant DNA methodologies, is rapidly leading to entirely new methods of treating disease. The early conception of this approach was gene therapy for single gene inherited disorders. The basic idea is compellingly simple: to treat a disease at the fundamental level of the DNA defect by inserting a normal copy of the gene into the diseased cells of a patient to correct the biochemical deficiency responsible for the disease symptoms. However, after 15 years of investigation by many laboratories, accomplishing this goal remains elusive. The strategy has been shown to work, in principle, for many disorders at the level of correcting a single deficient cell in tissue culture. In contrast, achieving appropriate transfer and regulation of genes, and sustaining the treatment, in whole animals has proven to be a formidable task. Moreover, although there have been a number of successes in mouse models, it has been much more difficult to scale up the methods to large animal models or humans. The large animal models that are the focus of most research (Haskins, Henthorn, Wolfe) with single gene disorders, are relatively rare and provide an experimental platform under disease conditions for understanding the problems of delivering genes successfully to a large mammal.

An example of the power of large animal models is the analysis of gene transfer to the brain to correct metabolic diseases that cause mental retardation in children. The challenge is to deliver the therapeutic gene throughout the brain because the disease affects many areas. Investigators have shown in the mouse that correction of Sly disease can be accomplished with some success, but there are still significant limitations.

The variety of diseases represented in large animal models of inherited disorders are an enormous resource for gene therapy studies aimed at surmounting the scientific barriers that are preventing human gene therapy from becoming a reality. However, these are less likely to be major targets for therapy in veterinary medicine because of their rarity and the "best medicine" being prevention by selective breeding or removal of carriers from the breeding stock. There are, nonetheless, a number of diseases of veterinary importance where gene transfer methods can potentially be used as primary or adjunctive treatment modalities. The original formulation of gene therapy has been expanded to the concept of molecular medicine, which can be stated as using recombinant DNA approaches to manipulate the biology of the organism for medical benefit. The types of disease that can potentially be helped by these methods include cancers, eye diseases, degenerative joint disease, neurological abnormalities such as epilepsy, metabolic diseases such as diabetes, and others. Application depends on thorough understanding of the underlying biochemical, cellular, and pathophysiological mechanisms of each disease. Studies in domestic animals may, in addition to providing potentially improved treatment, serve as a vital intermediary between rodent and human studies.