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ILAR Journal V36(3/4) 1994 [FORMERLY ILAR NEWS]
Advances in Gene Therapy
| Margaret Z. Jones. M.D., and Karen H. Friderici. Ph.D., were the chairs for the Michigan State University Genetics Program Symposium on Advances in Gene Therapy. Dr. Jones also chairs the ILAR News Editorial Panel. |
This issue of ILAR News focuses on state-of-the-art developments in genetic therapies. Often conceptualized as novel therapeutic approaches for inherited metabolic diseases, genetic therapies have been extended to acquired diseases as genetic mechanisms of non-inherited disorders have been defined. The advent of this revolutionary approach to the treatment of disease exemplifies the significant advances that arise from basic rather than targeted research. The dramatic leap from the laboratory to clinical applications has required unparalleled cooperation between scientists and clinicians. At the same time, the central role of animal models, as emphasized in this issue, places new demands for an understanding of these advances on the readers of ILAR News.
Four reviews, contributed by authors who participated in the September 1994 Michigan State University Genetics Program Symposium on Advances in Gene Therapy, held at Michigan State University and co-chaired by us, introduce the reader to the significant constraints pertaining to delivery systems for genetic therapy, therapies for inherited and acquired diseases, and unique considerations regarding different target cells and organ systems. The genetic therapies discussed in this issue are limited to those affecting somatic cells. For a discussion of germ-line genetic therapy, please see the review by Gordon (1991). Unintentional germ-line gene transfers during animal experiments involving in utero gene therapy was mentioned in a recent summary of the NIH Recombinant DNA Advisory Committee deliberations on the ethics of in utero gene therapy (Kolberg, 1995).
The reader is directed to the review by Mark Kay and Savio Woo (p. 47) for an introduction to viral vectors, in vivo and ex vivo methods of gene transfer, and stability of expression of transgenes. Metabolic diseases that are amenable to gene transfer are discussed. Introduction of genes into hepatocytes is described for the treatment of various inherited diseases.
Paul Robbins and Christopher Evans (p.53) review the progress toward gene therapy for arthritis. They introduce the concept of the usefulness of genetic therapies for individuals who may be genetically normal but have diseases in locations that are difficult to access with conventional therapies, such as joints. This idea is emphasized by their review of candidate therapeutic proteins for the treatment of arthritis. Genetic modification of cells to produce local or systemic therapeutic effects relevant to joint diseases are considered. Readers wilt find their discussion of animal models for arthritis especially useful. Genetic therapies for other acquired diseases are considered in Gilboa and Smith (1994) as well as Culver and Blaese (1994).
The central nervous system (CNS) also poses significant difficulties as a target for genetic therapies. Obstacles to treatment of CNS diseases are tabulated in Rosanne Taylor's article "Gene therapy for inherited neurological disease" on p. 56 of this issue (see also Friedman, 1994). Taylor pioneered the use of normal hematopoietic cells to deliver amounts of enzyme that ameliorated clinical symptoms and CNS lesions in fucosidosis dogs. Her studies demonstrated that "concentrations of gene products, which are within the range that can be provided by current gene therapy technology, can have potent effects when delivered to the site of neurological damage" (p. 58). Taylor indicates how important genetic therapeutic approaches are for the many neurological diseases that are unresponsive to available treatments. Viral and non-viral methods of gene delivery to the CNS and several cell types are discussed with respect to constraints imposed by the nervous system.
James Lupski discovered the genetic defect responsible for a common, autosomal dominant, human peripheral neuropathy, Charcot-Marie-Tooth disease (CMT). His discovery of a novel DNA duplication in affected patients was precedent-setting as a cause for chronic neurological diseases in humans. Benjamin Roa and Lupski review CMT and related diseases and discuss the prospects of gene therapy for these conditions. The wide range of technical information that impacts on the development of genetic therapies, especially for diseases like CMT, in which the expression is governed by gene dosage effects in addition to the inherited DNA rearrangement, is addressed. Their authoritative review stresses how much needs to be known about gene defects in order to make rational decisions about therapeutic approaches. Readers of ILAR News will be particularly interested in their discussion of related inherited demyelinating peripheral neuropathies in the Trembler mouse and other animal models.
Finally, we have included abstracts from other participants in the conference: "Dystrophin expression vectors for gene therapy of muscular dystrophy," by Jeffrey S. Chamberlain; "Viral vectors for hepatic gene therapy," by Mark A. Kay; "Advances in fragile X syndrome: Genetic and biochemical aspects," by Stephen T. Warren; and "Just caring: Ethical issues in germ-line genetic therapy," by Leonard M. Fleck.
These new approaches to the treatment of disease and determination of their feasibility and consequences largely depend on evaluation in animal models.
REFERENCES
Culver, K. W., and R. M. Blaese. 1994. Gene therapy for cancer. Trends in Genetics 10:174-178.
Friedmann, T. 1994. Gene therapy for neurological disorders. Trends in Genetics 10:210-214.
Gilboa, E. and C. Smith. 1994. Gene therapy for infectious diseases: The AIDS model. Trends in Genetics 10:139-144.
Gordon, J. 1991. Strategies for human germ-line gene therapy. Pp. 221-229 in Preimplantation Genetics, Y. Verlinsky and A. Kuliev, eds. New York: Plenum Press.
Kolberg. R. 1995. RAC tiptoes into new territory: In utero gene therapy. J. NIH Res. 7:37-39.