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Sinopsis
During the first half century of genetics, coinciding with the first half of this cen- tury, geneticists dreamt of the repair of genetic disease by altering or replacing defective genes. H. J. Muller wrote of the great advantages of mutations, "nanoneedles" in his apt term, for delicately probing physiological and chemical processes. In the same spirit, genes could be used to provide treatments of needle point delicacy. Yet, during this period no realistic possibility appeared; it remained but a dream. The situation changed abruptly at the half century. Microbial genetics and its offshoot, cell culture genetics, provided the route. Pneumococcus transformation showed that exogenous DNA could become a permanent part of the genome; yet attempts to reproduce this in animals produced a few tantalizing hints of success, but mostly failures. Transduction, using a virus as mediator, offered a better op- portunity. The fITSt reproducible in vivo gene therapy in a whole animal came in 1981. This was in Drosophila, with a transposable element as carrier. Flies were "cured" of a mutant eye color by incorporation of the normal allele, and the effect was transmissible, foreshadowing not only somatic, but germ line gene therapy. At the same time, retroviruses carrying human genes were found to be ex- tremely efficient in transferring their contents to the chromosomes of cultured cells.
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Reseña del editor
During the first half century of genetics, coinciding with the first half of this cen tury, geneticists dreamt of the repair of genetic disease by altering or replacing defective genes. H. J. Muller wrote of the great advantages of mutations, "nanoneedles" in his apt term, for delicately probing physiological and chemical processes. In the same spirit, genes could be used to provide treatments of needle point delicacy. Yet, during this period no realistic possibility appeared; it remained but a dream. The situation changed abruptly at the half century. Microbial genetics and its offshoot, cell culture genetics, provided the route. Pneumococcus transformation showed that exogenous DNA could become a permanent part of the genome; yet attempts to reproduce this in animals produced a few tantalizing hints of success, but mostly failures. Transduction, using a virus as mediator, offered a better op portunity. The fITSt reproducible in vivo gene therapy in a whole animal came in 1981. This was in Drosophila, with a transposable element as carrier. Flies were "cured" of a mutant eye color by incorporation of the normal allele, and the effect was transmissible, foreshadowing not only somatic, but germ line gene therapy. At the same time, retroviruses carrying human genes were found to be ex tremely efficient in transferring their contents to the chromosomes of cultured cells.
Reseña del editor
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.
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