Gene Therapy in Lung Disease PDF

PREFACE

When gene therapy became a clinical reality in the early 1990s, the possibilities seemed endless. Excitement was high and expectations were raised, leading to a generalized ‘‘suspension of disbelief.'' It seemed clear that the two most important pulmonary genetic diseases, cystic fibrosis and α1-antitrypsin disease, would soon be conquered and that a cancer cure was close behind. Alas, as with the monoclonal antibody revolution of the 1970s and the molecular biology revolution of the 1980s, real and substantial translation of therapies from ‘‘bench to bedside'' was a much more difficult and slow task than was originally anticipated.

Gene therapy is now in its adolescence and, like any good teenager, is suffering from the normal amount of angst and turmoil. The frenzy and hype of the early and mid-1990s were brought to a screeching halt by the general lack of successful clinical trials and by the death of a relatively normal teenager who had volunteered for a Phase I clinical trial to treat a metabolic liver disorder. Suspension of disbelief was replaced with ‘‘presumption of disbelief '' and a generally negative perception.

Somewhere between these two extremes lies the truth. In actuality, gene therapy has made tremendous strides over its short 12-year lifetime. First, gene therapy techniques have been applied successfully to the study of cell biology and animal models of disease. The ability to deliver genes to animals in a controlled and specific manner has revolutionized our ability to study disease processes. Second, many clinical trials have been performed and analyzed. Although dramatic clinical efficacy has not yet been shown, almost all of the human trials conducted were dose-finding Phase I trials designed to evaluate toxicity, not responses. It is therefore not surprising that clinical success stories have been unusual to date. One major finding of the last decade is that gene therapy has proven to be a remarkably safe and nontoxic approach. Thousands of patients have undergone gene therapy with very little toxicity. Third, a great deal of research has gone into studying, characterizing, and developing new vector approaches to optimize gene transfer. These studies will define the shape of gene therapy trials in the future.

Another interesting benefit of gene therapy is that it has inspired physicianscientists, not working for pharmaceutical or drug companies, to design and conduct clinical research aimed at delivering useful treatments to patients. Many of us have dreamed of developing and testing new therapies, but for the most part, this has been within the purview of industry, not academia. Many of the early gene therapy trials were initiated and conducted by individual groups of academic investigators, with funding from the National Institutes of Health, allowing unprecedented freedom. This academic orientation has allowed researchers to define more freely the benefits and significant limitations of current technology than might be possible in a traditional pharmaceutical environment. This dissemination of knowledge about the limitations of the ‘‘first-generation'' vectors has been critical in spurring the development of improved or new technologies. Thus, although the early years of gene therapy were dominated by first-generation adenoviral and retroviral vectors, more recently ‘‘gutless'' third-generation adenoviruses, adeno-associated viral vectors, and lentiviral vectors have moved to center stage.

Gene therapy of lung disease has always played a central role in gene therapy and has often led the field. Although a volume of this series devoted to gene therapy for diseases of the lung was published in 1997, enough has changed since then to warrant an update. After a general historical overview, the book is divided into three parts. The first presents a detailed discussion of each of the major vector systems being used in lung gene therapy today. These include adenoviral and adeno-associated viral vectors, liposomes, and replicating vectors. Also included is an examination of advances in the targeting of gene therapy vectors. The second part focuses on the use of gene therapy to study lung disease processes (primarily in animal models) such as cytokine behavior, infection and immunity, and fibrosis. The last part describes the use of gene therapy to treat specific lung diseases such as lung cancer, mesothelioma, cystic fibrosis, pulmonary vascular diseases, α₁-antitrypsin disease, acute lung injury, and lung transplantation.

I would like to thank the chapter authors for their willingness to participate in this endeavor and for their outstanding contributions. I have been honored to work with Dr. Claude Lenfant, who asked me to edit this volume and who has been extremely supportive. I have no doubt that gene therapy will be an extremely valuable part of the therapeutic armamentarium of the 21st century. Dr. Lenfant and the authors of these chapters are the people who will ensure that this will happen.