Immunological hurdles to lung gene therapy.
Gene delivery has the potential to offer effective treatment to patients with life-threatening lung diseases such as cystic fibrosis, alpha1-antitrypsin deficiency and lung cancer. Phase I/II clinical trials have shown that, in principle, gene transfer to the lung is feasible and safe. However, gene expression from both viral and non-viral gene delivery systems has been inefficient. In addition to extra- and intracellular barriers, the host innate and acquired immune system represents a major barrier to successful gene transfer to the lung. Results from studies in experimental animals and clinical trials have shown that inflammatory, antibody and T cell responses can limit transgene expression duration and readministration of the gene transfer vector. We will review here how the development of pharmacological and/or immunological agents can modulate the host immune system and the limitations of these strategies. A better understanding of the immunological barriers which exist in the lung might allow for a more sustained expression of the transgene and importantly help overcome the problem of readministration of viral vectors.
Ferrari
S
S
Department of Gene Therapy, National Heart and Lung Institute, Imperial College Faculty of Medicine, London, UK. stefano.ferrari@ulss12.ve.it
Griesenbach
U
U
Geddes
D M
DM
Alton
E
E
D019138:Antibodies, Blocking / Q000276:immunology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007249:Inflammation; D008168:Lung / Q000276:immunology*; D008171:Lung Diseases / Q000276:immunology / Q000628:therapy*; D008264:Macrophages / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D017211:Treatment Failure
D019138:Antibodies, Blocking; D007166:Immunosuppressive Agents