Gene Therapeutics

The best theories are usually those that explain much in simple terms. There is a certain beauty to such ideas. Physicists in search of a "theory of everything," for example, like to admire the aesthetic qualities of their theoretical constructs. The reasoning behind gene therapy is attractive for this very reason. It is simple: if a genetic disease is caused by a dysfunctioning gene, then the disease state can be corrected by giving the patient the normal, functioning gene. Although gene therapy was initially formulated to treat single gene defects, it now holds promise for a wide range of disorders, including cancer, heart disease, and degenerative neurologic disorders. Potentially, it could be a "treatment of everything," or at least of many things. Initial attempts at gene therapy involved the genetic modification of cells in culture, which were then transplanted back into the body. This is known as an indirect, or ex vivo, approach. The focus of this book is the simpler, in vivo approach that involves the direct introduction of genes into the body without cell transplantation.
The direct approach resembles conventional pharmaceutical delivery methods and promises to be much less expensive than the indirect, ex vivo approaches. There is a certain elegance to its simplicity. Of course, patients care only for alleviation of their disease. They are concerned with risk versus benefit ratios, not with the aesthetics of the theoretical underpinnings of their treatment. Only the results of clinical trials will enable us to judge the clinical value of direct gene therapeutics. However, the tremendous progress reported in this book suggests that this approach has a very promising future. The book is divided into three sections. The first provides a scientific background for the concepts involved in gene therapy that include a history of previous experiments, and the production of mouse genetic models. The basic tenets of expression are explored in one chapter that addresses transcription and another chapter that addresses the post-transcriptional elements of expression. The second section covers the spectacular new methodologies and how these systems work.
The methods includes naked DNA, oligonucleotides, calcium phosphate precipitation, polylysine-complexes, adenovirus-polylysine DNA complexes, liposomes, electroporation, and particle bombardment. The third section covers applications for specific organs and diseases. They encompass gene delivery to the CNS skeletal muscle, heart, liver, lung, thyroid and joints. Applications for cardiovascular disease, brain tumors, immunization, arthritis, cystic fibrosis, and Duchenne muscular dystrophy are discussed. Pharmacokinetic considerations are also covered in the chapter by Fred Ledley.