Towards gene therapy for inflammatory and infective pulmonary diseases

Pneumonia is responsible for unacceptably high mortality rates among specific populations of patients, despite the use of conventional antibiotics and improvements in critical care. New treatments for severe pulmonary infection are therefore required. Manipulation of host defence genes using targeted gene therapy seems a logical strategy for severe pulmonary infection, and several groups have recently demonstrated that therapeutic genes can protect the healthy lung against the subsequent development of experimental pneumonia. This article reviews the problems facing the development of gene therapy for human pneumonia, with particular reference to safety issues and to the physical and biological barriers limiting efficient delivery of therapeutic transgenes to cells in the lung. The strengths and weaknesses of vectors currently available for pulmonary gene therapy are also considered, with emphasis on recent developments relating to adenovirus, adeno-associated virus and non-viral vector systems. Thereafter the specific gene therapy strategies used either to enhance clearance of pneumonia in laboratory animals or to immunise rodents against subsequent pulmonary challenge with human pathogens are discussed and placed in the context of future potential applications to human pneumonia.