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Gene therapy in large animal models of human genetic diseases. Introduction.

Amajor challenge to the medical sciences is the large number of disorders that are primarily genetic in origin or that involve a genetic predisposition to disease-producing factors in the environment. These disorders include a wide variety of debilitating and fatal illnesses for which few effective methods of treatment or prevention are available. Among the most common diseases in which genetic abnormalities play a role are congenital malformations, metabolic disorders, and cancer. Genetic variations also infl uence individual responses to pathogens and drugs. The structure and function of most genes in animals are homologous to those in humans, thus many genetic diseases that occur in humans also occur in animals. Gene mutations usually cause similar biochemical dysfunctions, resulting in pathologic changes at the molecular, cellular, organ, and organism levels. For these reasons, the knowledge gained through research in animals can be of direct benefi t to human as well as animal health. There have been dramatic advances in the science of genetics in recent years. The techniques of molecular biology have made it possible to understand the underlying mechanisms of genetic disease at the level of DNA, RNA, and protein molecules. The completion of the genome sequences of the human, mouse, dog, cat, and a growing list of other species as well as advances in genomics and related sciences represent the beginning of a new phase of understanding in which it will be possible to delineate the entire genetic program of individual types of cells and ultimately of whole tissues. Furthermore, these advances offer the prospect of correcting genetic defects and disease susceptibilities in animal and human patients through gene replacement therapy, manipulation of genetic pathways, engineering of stem cells, and delivery of recombinant proteins. The realization of practical benefi ts to animal and human health will depend on a great deal of future research. The increasing number and variety of transgenic, induced mutant, and naturally occurring animal models of genetic disease are vital for identifying new genes that cause disease, for understanding the cellular and molecular mechanisms of genetic diseases, and for elucidating the genes involved in diseases with complex inheritance patterns. A major use of such models is translational—they help move gene therapy strategies from proof of concept in cells and rodent models toward human clinical trials by enabling the investigation and solution of problems in scale-up and treatment of individual animal patients. The participation of veterinarians in these investigations is critical because they have the knowledge and skills in animal physiology, pathology, medicine, and surgery that enable them, with the proper scientifi c training, to effectively investigate important aspects of the pathogenesis and treatment of genetic and gene-infl uenced diseases in animal homologues of human disorders. Selection of Topics and Organization of This Issue