Clinical Gene Therapy for Nonmalignant Disease Thomas A. Ratko, PhD, Joseph P. Cummings, PhD, John Blebea, MD, Karl A. Matuszewski, PharmD Gene therapy is envisioned as a potentially definitive treatment for a variety of diseases that have a genetic etiology. We reviewed trials of clinical gene therapy for nonmalignant, single-gene, and multifactorial disorders and infectious diseases, and found limited evidence suggesting that gene therapy may benefit pa- tients who have severe, combined, immunodeficiency disorder; cystic fibrosis; coronary artery disease or peripheral arterial dis- ease; or hemophilia. Effective gene therapy requires the targeted transfer of exogenous genetic material into human cells and the subsequent regulated expression of the corresponding gene product. Because no phase 3 randomized controlled trials have been completed that fulfill these criteria, it is difficult to corre- late signs of clinical benefit with the administration of gene ther- apy in any disease. Additional clinical and basic research is needed to determine the future role of gene therapy. Am J Med. 2003;115:560 –569. ©2003 by Excerpta Medica Inc. G ene therapy, the transfer of genetic material into human cells to treat a disease, differs from phar- macological therapy in that it seeks to perma- nently correct a disease-associated genotypic defect rather than merely treat the phenotypic expression. Whereas drug therapy typically requires multiple doses to suppress the signs and symptoms of an illness, correction at the gene level would, presumably, make subsequent interventions unnecessary. Because somatic cells and not germ cells are targeted, gene therapy affects the patient and not the patient’s offspring. Developments in molecular biology in the early 1970s yielded the basic knowledge and tools that permitted the first sanctioned clinical gene therapy study in the early 1990s (1). Because of potential dangers of gene therapy, investigators were cautious in patient selection and appli- cations. By 1995, approximately 100 gene transfer proto- cols had been approved by the National Institutes of Health Recombinant DNA Advisory Committee for clin- ical investigation (2). Subsequently, more than 400 clin- ical gene therapy protocols have been approved in the United States, about 75% of all protocols approved worldwide (3). At present, published clinical reports on gene therapy comprise small phase 1 or 2 trials. No peer-reviewed data from a phase 3 trial are available that demonstrate the clinical effectiveness of gene therapy in any disease. We review the current status of this field as it pertains to non- malignant, single-gene, and multifactorial disorders and infectious diseases. LITERATURE SEARCH We searched MEDLINE through September 2002 to identify English-language review articles of studies in- volving human subjects that were published during the previous 4 years, using the key words gene therapy. This search yielded more than 900 citations, including many that were not relevant. Seventy-three review articles were obtained and their references were examined to identify additional pertinent reviews. The “related articles” func- tion of the search engine also was used to find other arti- cles relevant to specific topics within the field. Primary English-language references to clinical trials that were published in the preceding 7 years were also obtained through a MEDLINE search, using the key words gene therapy. The search yielded 187 citations that were re- viewed for their relevance. The “related articles” function was used to identify additional references that might have eluded the initial search, and the bibliography of each article obtained was examined. The National Institutes of Health Office of Biotechnology Activities Recombinant DNA and the Gene Transfer websites were also used as sources of background information (2). The Wiley Jour- nal of Gene Medicine Clinical Trial website was accessed to obtain information on clinical trials worldwide (3). A total of 121 relevant articles were obtained, including reviews, original works, and related publications that provided background information. Details of original clinical trials were organized in evidence tables according to major disease categories. A modified grading system was used to categorize the levels of evidence by study design (4,5). Somatic gene therapy is considered in the context of gene delivery vehicles and the conditions that may be treated. Data from randomized controlled trials (type I evidence) are generally considered to provide the most reliable evidence of clinical effectiveness, as compared with data from uncontrolled open series, cohort studies, retrospective analyses, or case reports. The evidence grad- ing system measures the strength of the available data From Clinical Knowledge Services (TAR, JPC, KAM), University HealthSystem Consortium, Oak Brook, Illinois; and the Section of Vas- cular Surgery (JB), Temple University Hospital, Philadelphia, Pennsyl- vania. Requests for reprints should be addressed to Thomas A. Ratko, PhD, Technology Assessment Group, University HealthSystem Consortium, 2001 Spring Road, Suite 700, Oak Brook, Illinois 60523-1890, or ratko@uhc.edu. Manuscript submitted March 13, 2003, and accepted in revised form July 4, 2003. 560 © 2003 by Excerpta Medica Inc. 0002-9343/03/$–see front matter All rights reserved. doi:10.1016/S0002-9343(03)00447-9