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Gene Therapy for the Management of Pain: Part I: Methods and Strategies

A RECENT report from the Recombinant DNA Advisory Committee lists 393 approved human gene therapy protocols (www.od.nih.gov/oba/documents.htm). Of these, 33 are for infectious diseases, 49 for monogenic diseases (mostly cystic fibrosis), 237 for cancer, 35 for other disorders, and the remainder for nontherapeutic trials. Despite the serious nature of pain, both in terms of human suffering and economic cost, there are no human gene therapy protocols that target it. Could it be that the biologic basis of pain is too ill defined to apply the state-of-art gene therapy to it? In recent years, significant progress has been made in our fundamental understanding of the neurobiology of pain. In parallel, detailed molecular biologic characterization of many of the receptors and ion channels playing significant roles in nociception have become available. Although in its infancy, gene therapy, or the translational clinical application of the molecular biologic revolution, has fundamentally changed the way we study basic biologic processes and clearly will impact our clinical management of diverse diseases, including pain. This review summarizes recent developments in gene therapy and demonstrates the possibility of gene therapy for the management of pain. This is a broad topic requiring expertise in diverse areas of science and medicine. As such, diverse literature spanning basic molecular biology, viral vectors, antisense oligonucleotide, and pain literature was reviewed. We have strived to create a review with a dual mission of serving as a didactic document and as a document that will serve as a reference for active investigators in this area of science. Most importantly, we hope that this review will stimulate the interest of the readers to further explore the genetic approach to pain management. In Part I, we begin with a discussion of strategies for gene therapy, followed by an introduction of the fundamental methods and technologies (both viral and nonviral) available for gene therapy and transfer. Part II of the review, to be published subsequently, will describe potential nociceptive targets for the methods and strategies of gene therapy described in this review. The pathways of nociception are not summarized; however, there are many excellent reviews summarizing recent developments in our understanding of pain mechanisms. An authoritative review covering neuronal pathways to molecules mediating pain was recently published. Our goal is to minimize overlap with these reviews by focusing on information pertinent for gene therapy considerations. Readers unfamiliar with the basic molecular biologic concepts are referred to an excellent primer on molecular biology recently published in ANESTHESIOLOGY or chapters in standard reference books. Specific protocols for routine molecular biologic techniques can be found in any of the laboratory manuals, and practical methods for creating genetransduction viral vectors can be found in references cited in table 1. Reviews by Eck and Wilson, Andersen, and Kay et al. provide excellent general overviews of gene therapy. Lastly, clinical trials using gene therapeutic agents are subject to full federal regulations, as with any new investigational drug. Moreover, gene therapy protocols are subject to an additional oversight by the federal recombinant DNA advisory committee. Further information and guidelines for developing a human clinical trial protocol, as well as an updated list of active gene therapy trials, can be found at the National Institutes of Health web site referenced above. *Assistant Professor, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Hospital. †Assistant Professor, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center. ‡Senior Instructor, Department of Anesthesiology, §Associate Professor, Departments of Anesthesiology, Pharmacology, and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York.