Fred H. Gage

Lymphokine gene therapy of cancer

A novel method of tumor immunotherapy is described comprising the genetic modification of cells resulting in the secretion of cytokine gene products to stimulate a patients immune response to tumor antigens. In one embodiment, autologous fibroblasts genetically modified to secrete at least one cytokine gene product are utilized to immunize the patient in a formulation with tumor antigens at a site other than an active tumor site. In another embodiment, cells genetically modified to express at least one tumor antigen gene product and to secrete at least one cytokine gene product are utilized in a formulation to immunize the patient at a site other than an active tumor site.

Neural Stem Cell Isolation, Characterization and Transplantation

During development, nerve cells in the mammalian central nervous system (CNS) are generated by the proliferation of multipotent stem or progenitor cells that migrate, find their site of final destination and ultimately terminally differentiate. However, the mechanisms for development of diversified cell types in the CNS and the environmental stimuli involved in these processes are not well understood. In analogy with the hematopoietic system, it has been proposed that during CNS development, a self-renewing population of stem cells gives rise to a more restrictive population of progenitor cells. However, the existence of these elusive progenitor cells has not been proven due to the unavailability of specific phenotypic markers. In the adult brain only a small number of stem cells exist and they differentiate into neurons at specific neurogenic sites at a slow rate (Morshead et al., 1994; Kuhn et al., 1996).

Mobilizing Endogenous Stem Cells

Over the last 50 yr, the long-held dogma that neurogenesis stops at birth has been gradually modified to allow specific exceptions to the rule. In many mammalian species, new neurons are continually added to the adult olfactory bulb (1) and hippocampus (2–5). As more information is gathered, additional sites may be found that are unique to individual species (6). Although natural neurogenic processes respond in a limited manner to damage in the CNS (7–9) the inability of the adult brain to regenerate fully following disease or injury still provides a concrete example of how the dogma holds true from a clinical point of view. In this context, the insight gained in defining neurogenic mechanisms in the adult may be relevant to central nervous system (CNS) repair since the successful therapeutic approaches will ultimately depend on the precise modulation of an extensive regulatory network.

Future Prospects of Gene Therapy for Treating CNS Diseases

In the last several decades, enormous gains have been made in our understanding of the pathogenesis of various human diseases. By understanding the biochemical, molecular, and genetic mechanisms through which a disease state manifests itself, it becomes possible to develop rational strategies for therapeutic intervention. In addition to providing insight into disease mechanisms, studies using molecular biology have provided a tool, gene therapy, through which it is possible to induce a cell to make a specific protein that could interfere with the disease process. Gene therapy provides for a local, regulated delivery of the therapeutic gene product, thereby avoiding some of the systemic side effects of drug therapies. Gene therapy has been investigated with some success in several organ systems and this review discusses efforts to use gene therapy in central nervous system (CNS) diseases. Considerations for using gene therapy and the benefits of various delivery approaches are addressed. The potential efficacy and drawbacks of gene therapy for CNS disease are discussed in light of advances in preclinical research. Finally, the future prospects for the use of gene therapy in the clinic are discussed in terms of safety, ethical considerations, and public opinion.