Gene Therapy for Pulmonary Diseases

Gene therapy for pulmonary disease has attracted a great deal ofattention since the first report of successful gene delivery 10 yearsago. Potential indications for gene therapy include chronic illnessessuch as cystic fibrosis and α1-antitrypsin deficiency, and acute illnesses such as acute transplant rejection andchemotherapy-induced lung injury. The key technological impediment tosuccessful gene therapy is vector optimization. Viral vectors, including adenovirus and adeno-associated virus, have relatively lowefficiency in vivo. In addition, adenovirus has beenassociated with a brisk inflammatory response and limited duration ofexpression in the lung. Nonviral vectors, particularly liposomes, havealso been tried, with limited expression efficiency and some toxicity. Although work is ongoing to improve adenoviral and adeno-associatedviral vectors and test other viral and nonviral vectors, an idealvector has not yet been identified. Several important barriers tosuccessful gene therapy, including the host inflammatory response, promotor down-regulation, tissue-specific targeting, and physicalbarriers to gene delivery in the airway, will need to be overcome. Despite these daunting problems, several human gene therapy trials havebeen completed, using adenovirus, adeno-associated virus, andliposomes. In general, these trials have been focused on safety, andhave shown that there is dose-dependent inflammation in response toadenovirus. Adeno-associated virus appears to cause littleinflammation. Demonstration of successful gene delivery andtranscription has been quite variable in human trials. In general, thelevel of expression of transgene appears to be quite low. In summary, although there is great promise for gene therapy in the lung, significant challenges remain in translating this technology tosuccessful human therapy.