Dr. Ronald G. Crystal, Professor of Medicine and Genetic Medicine, and Director, Institute of Genetic Medicine, Weill Medical College of Cornell University, New York, summarized the main concepts of genetic medicine and the challenges to achieving successful gene therapy. He noted that gene therapy is essentially a "drug" delivery system for transferring genes to cells via a delivery vehicle (a vector) to change the genetic repetition in cells, organs, or systems and to elicit a "cure." The targets for gene therapy are hereditary diseases, a focus of attention in the mid-1980s, and acquired diseases related to multiple genes, the current focus of genetic research. Two methods of gene therapy are ex vivo, which is used widely for diseases of the blood, and in vivo, a current area of emphasis, for diseases of organs, such as the heart and lung. Genes may be inserted into the genome (primarily for hereditary diseases) or extrachromosomally into the cell nucleus. Viral vectors are more effective than nonviral vectors, and the selection, use, and efficacy of a viral vector (adenovirus, adeno-associated virus, or retrovirus) depend on the application.

Dr. Crystal noted that the adenovirus, which causes the common cold, is the gold standard of vectors and is ideal for situations requiring high doses over a short period. Since 1989, it has been used in research on lung diseases (e.g., cystic fibrosis) and blood diseases (to stimulate proliferation and differentiation of red blood cells). The major challenge, particularly for lung diseases, has been to overcome a host's defenses and to secure long-term expression of a gene. Researchers also are exploring use of "regenerative" gene therapy, or repeated short-term treatments with a gene (e.g., to "cure" baldness or chemotherapy-induced alopecia). Dr. Crystal elaborated on the use of transient gene therapy using a master-switch gene to induce angiogenesis (formation of new blood vessels). Based on successful animal studies which demonstrated the feasibility, safety, and efficacy of this approach, researchers are conducting Phase I clinical studies, in conjunction with conventional bypass surgery, in 15 individuals to evaluate this approach for therapeutic angiogenesis of ischemic heart disease. Other studies are focused on peripheral arterial disease.

Dr. Crystal commented on the need to address the theoretical risks of gene therapy, the public's concerns, and the regulation of this research by review boards and national committees and agencies. He noted that about 1,000 patients have been involved in hundreds of gene studies and that these studies have resulted in correction of otherwise fatal disorders but also, unfortunately, resulted in a patient's death. The key challenges in translating the results of gene therapy from the laboratory to the clinic include:

• Predicting the potential of this therapy in humans (which differs from that in experimental animals)
• Producing clinical-grade reagents
• Establishing a profile for adverse events from treatment
• Ensuring adequate regulation and oversight
• Obtaining sufficient research funding (e.g., one clinical trial costs approximately $1.5-2.0 million).

Dr. Crystal emphasized that human studies are critically important for realizing the full potential of gene therapy. The future prospects for this therapy are unlimited as scientists continue to study the 75,000 genes (now estimated for the human body) and to match gene strategies with disease targets.