The Challenge of Using Gene- or Cell-Based Therapies to Treat Lung Disease
Authors: Ronald G Crystal
Journal: Molecular Therapy (2012)

As the organ of gas exchange, the human lung is designed to bring inspired air and venous blood into close approximation, allowing oxygen to be transferred to red blood cells coursing through the alveolar walls. In exchange, carbon dioxide, the waste gas of metabolism, is eliminated from the body. To accomplish this, the human lung has evolved as a complex structure with a complicated biology that is as yet only partially understood. This complexity, while a marvel from a biological viewpoint, is a challenge for the gene and cellular therapists who have directed their investigations to use gene therapy to cure lung disease and stem/progenitor cell therapy to reconstruct damaged or lost lung. Two reviews in this issue of Molecular Therapy—one from the McCray laboratory,1Oakland M Sinn PL McCray Jr PB Advances in cell and gene-based therapies for cystic fibrosis lung disease.Mol Ther. 2012; 20: 1108-1115Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar the other from the Weiss group2Lau AN Goodwin M Kim CF Weiss DJ Stem cells and regenerative medicine in lung biology and diseases.Mol Ther. 2012; 20: 1116-1130Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar—focus on these issues and the state of the art. The review from the McCray laboratory summarizes the status of using gene transfer to restore airway epithelial cyclic adenosine monophosphate–mediated Cl− channel activity in the airway epithelium of individuals with cystic fibrosis (CF). To accomplish this, the normal human CF transmembrane conductance regulator (CFTR) complementary DNA (cDNA) has to be transferred to, and appropriately expressed in, more than 10% of 1–2 m2 of airway epithelium distributed over 223 dichotomously branching airways of 1 cm to 50 mm in diameter. As the review details, this is not a simple task. Not only do the vectors have to be safe (no insertional mutagenesis, no significant adverse host responses to the vector delivery system), but expression must be persistent and control of expression of the CFTR gene must be similar to that of the normal airway epithelium. Arrayed against achieving this are the formidable physical and immune host defense barriers that have evolved to protect the lung from a hostile environment. These defenses not only limit the ability to transfer the CFTR cDNA to the airway epithelium, but have evolved to eliminate viruses and foreign macromolecules from the lung; in other words, the lung's defenses are allied against the gene therapist's vectors. This was the lesson learned from the adenovirus vector gene therapy trials for CF carried out by our laboratory and by the Wilson and Welsh/Zabner/Genzyme groups almost two decades ago.3Zabner J Couture LA Gregory RJ Graham SM Smith AE Welsh MJ Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis.Cell. 1993; 75: 207-216Abstract Full Text PDF PubMed Scopus (610) Google Scholar, 4Crystal RG McElvaney NG Rosenfeld MA Chu CS Mastrangeli A Hay JG et al.Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis.Nat Genet. 1994; 8: 42-51Crossref PubMed Scopus (791) Google Scholar, 5Zuckerman JB Robinson CB McCoy KS Shell R Sferra TJ Chirmule N et al.A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis.Hum Gene Ther. 1999; 10: 2973-2985Crossref PubMed Scopus (130) Google Scholar, 6Harvey BG Leopold PL Hackett NR Grasso TM Williams PM Tucker AL et al.Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus.J Clin Invest. 1999; 104: 1245-1255Crossref PubMed Scopus (202) Google Scholar We found that it is possible to use viral vectors to transfer the CFTR gene to the airway epithelium and “cure” CF in a limited region of the nasal or airway epithelium, but that the innate and acquired immune defenses of the lung eliminate the foreign gene within a short time, limiting the period of effectiveness of the therapy. Subsequent efforts in the 1990s to make vectors “stealth” failed to circumvent the lung's host defenses.7Wilson JM Adenoviruses as gene-delivery vehicles.N Engl J Med. 1996; 334: 1185-1187Crossref PubMed Scopus (432) Google Scholar However, as Oakland et al.1Oakland M Sinn PL McCray Jr PB Advances in cell and gene-based therapies for cystic fibrosis lung disease.Mol Ther. 2012; 20: 1108-1115Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar nicely catalog, studies by many laboratories over recent years have led to significant advances in new vector types and design that may circumvent host defenses and mediate persistent expression in the airway epithelium. There are also new strategies for vector delivery, and better experimental animal models relevant to CF have been developed. Thus, much progress has been made, and several investigators continue to push forward the frontiers of gene therapy to correct CF. But is gene therapy for CF feasible in the near future? After all, the gene therapy field has had recent remarkable successes in therapy for blindness, immunodeficiency, and hemophilia. As much as I would like to see CF gene therapy added to this list, with the advantage of more than 20 years of hindsight, I think successful gene therapy for CF is still a long way off. The physical and host defense barriers of the lung are simply too great. While I applaud the efforts and admire the creative new approaches, it is doubtful there will be successful clinical trials for CF in the next decade. This does not mean that the McCray and other laboratories toiling away at CF gene therapy should give up, because their work is critical for continued progress toward therapy for CF, but they and the CF community should not expect a gene therapy “cure” in the near or midterm future. If correcting the lung with gene transfer is tough, why not just rebuild the lung? This is the focus of the Weiss review. Lung transplantation, while limited by the donor pool and challenges with chronic rejection, is clearly successful; that is, if a patient has chronic lung failure, exchanging a destroyed lung with normal lung can reestablish normal gas exchange. But could this be achieved by regenerating lung de novo from stem/progenitor cells? As the Weiss review1Oakland M Sinn PL McCray Jr PB Advances in cell and gene-based therapies for cystic fibrosis lung disease.Mol Ther. 2012; 20: 1108-1115Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar details, there has been an intense focus on defining the stem/progenitor cells of the lung and developing strategies to regenerate normal lung tissue. If successful, this would be applicable not only to CF, but also to most of the chronic lung diseases, including chronic obstructive pulmonary disease (emphysema and chronic bronchitis), the interstitial (fibrotic) lung disorders, and pulmonary hyper­tension. Although regenerative lung research is far less mature than gene therapy for the lung, significant advances have been made. As comprehensively summarized in the review, there have been many new insights into the biology of lung regeneration, including lung-related endogenous progenitors, circulating endothelial progenitors, bone marrow–derived mesenchymal stromal cells, embryonic stem cells, induced pluripotent stem cells, and ex vivo lung bioengineering. Is lung regeneration ready for prime time? If the history of gene therapy is a guide, there undoubtedly will be some clinical trials of lung regeneration in the next 5 to 10 years. Will they be successful? The challenges are formidable, and the biological understanding too limited, at least for now. First, despite the exciting discoveries made over the past decade, stem/progenitor cells are still “black boxes” for which science has just scratched the surface of understanding. Second, the lung is a very complex organ, with complicated alveolar structures and airways and two different circulations. Furthermore, it is a mechanical organ; without periodic respiration, carbon dioxide cannot be eliminated. Superimposed on all this are the pulmonary immune/inflammatory cell host defenses, neural input to modulate airway and vascular tone and to control respiration, and local and circulating mediators and cell-to-cell crosstalk that modulate lung cell biology. Finally, there is the issue of control of the cells in the regenerated tissue. Once transplanted into the human, these cells could go awry; this could result in not only disordered tissue but—in the extreme example—malignant transformation.8Kiuru M Boyer JL O'Connor TP Crystal RG Genetic control of wayward pluripotent stem cells and their progeny after transplantation.Cell Stem Cell. 2009; 4: 289-300Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Thus, I urge my lung-regeneration colleagues to tread carefully toward the clinic and to focus on the biology—in other words, get it right before jumping to “cures.” One suggestion is in order. The lung regenerative–medicine field should join forces with the lung gene therapy field to develop strategies to use gene transfer to provide control for the transplanted cells destined to create new lung tissue8Kiuru M Boyer JL O'Connor TP Crystal RG Genetic control of wayward pluripotent stem cells and their progeny after transplantation.Cell Stem Cell. 2009; 4: 289-300Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar (Figure 1). Also, where relevant, genetically modified transplanted regenerative tissues could be used as factories to provide therapeutic products locally to treat lung disease. Are the challenges too great for lung gene therapy and/or regenerative medicine? Should we surrender to the biological complexity of the lung? Or do these strategies show promise? The McCray and Weiss reviews are excellent summaries of the state of the art in gene and stem/progenitor therapies for lung disease and will serve as useful overviews for practitioners in the art. The challenge for both fields is to focus on understanding the biology of the lung and how these technologies can be put to use in treating lung disease. Just like organ transplantation and monoclonal antibodies, gene therapy and regenerative medicine are technologies that are revolutionary in concept and have the potential to provide major therapeutic advances. But, as with transplantation and monoclonal antibodies, the road to clinical cures for lung gene therapy and regenerative medicine is littered with obstacles. These will be overcome, but it will take much time and hard work in the laboratory before they will be successfully used to treat human lung disease. Advances in Cell and Gene-based Therapies for Cystic Fibrosis Lung DiseaseOakland et al.Molecular TherapyJune, 2012In BriefCystic fibrosis (CF) is a disease characterized by airway infection, inflammation, remodeling, and obstruction that gradually destroy the lungs. Direct delivery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to airway epithelia may offer advantages, as the tissue is accessible for topical delivery of vectors. Yet, physical and host immune barriers in the lung present challenges for successful gene transfer to the respiratory tract. Advances in gene transfer approaches, tissue engineering, and novel animal models are generating excitement within the CF research field. Full-Text PDF Open ArchiveStem Cells and Regenerative Medicine in Lung Biology and DiseasesLau et al.Molecular TherapyJune, 2012In BriefA number of novel approaches for repair and regeneration of injured lung have developed over the past several years. These include a better understanding of endogenous stem and progenitor cells in the lung that can function in reparative capacity as well as extensive exploration of the potential efficacy of administering exogenous stem or progenitor cells to function in lung repair. Recent advances in ex vivo lung engineering have also been increasingly applied to the lung. The current status of these approaches as well as initial clinical trials of cell therapies for lung diseases are reviewed below. Full-Text PDF Open Archive