Genetic disorders commonly treated by
pediatric and adult pulmonary physicians have been targets of great interest in the field of gene therapy, and more recently in the field of stem cell therapy as well. Most notably in the early history of human gene therapy trials, a broad initiative led by the Cystic Fibrosis (CF) Foundation drove the efforts to bring new gene therapy vectors into clinical use. Because of this, the first human use of both recombinant adenovirus (rAd) and recombinant adeno-associated virus (rAAV) vectors occurred in CF patients in 1993 and 1995, respectively (Crystal et al.
; Flotte et al.
). Many lessons were learned about vector safety and duration of effect from those early trials, even though neither has led to the development of clinically effective therapies at this point. Gene and cell therapy approaches for CF remain an active topic of research in many laboratories as more varied approaches including integrating lentivirus vectors and novel approaches to airway and lung regeneration. Most notably, artificial tracheas repopulated with human stem cells have been used clinically in Scandinavia to treat patients with surgically irreparable damage to the trachea, providing a potential proof of concept for more extensive cell-based repopulation of the respiratory tract that could eventually be applied to airway diseases like CF (Anonymous, 2011
Meanwhile, the attention to treatment for genetic disorders within the practice of pulmonologists has broadened to include genetic emphysema due to alpha-1 antitrypsin (AAT) deficiency and genetic disorders that contributed to over 5% of cases of sudden infant death syndrome (SIDS) (Boles et al.
). Clinical protocols with rAAV-based vectors for AAT deficiency have progressed through phase 2 and remain currently active. This disorder mimics other deficiencies of secreted serum proteins such as hemophilias. Meanwhile, the advent of newborn screening for metabolic diseases has revealed populations of patients with disorders of fatty acid oxidation (FAO), the most frequent of which is medium chain acyl-CoA dehydrogenase (MCAD) deficiency. Without this screening, affected individuals would likely succumb to SIDS. Interventions to treat the genetic basis of FAO disorders seem more likely to affect the outcome in such infants, as compared with the previous approach to familial cases of SIDS, which was home apnea monitoring. The rAAV-based proof-of-principle studies for FAO disorders have generally been aimed at correction of cardiac and skeletal muscle (which metabolizes the largest proportion of fatty acids), the liver (which can use FAO to help generate ketones as a protection against fasting hypoglycemia), or the entire body (which could assist with both the accumulation of toxic metabolites and the lack of ATP generation caused by the disorder).
Taken together, the experiences garnered from attempts to develop gene and cell therapy for inherited diseases affecting the lung and ventilator control have both contributed to and benefited from technological advances in the field more generally. Genetic diseases in this category have been somewhat difficult as targets in the past because of the dearth of truly faithful animal models of CF and AAT deficiency and, in the case of CF, because of the truly recalcitrant nature of the target cell itself, the airway epithelial cell. Airway epithelial cells are actively replicating, making gene therapy with nonintegrating systems more challenging, and have evolved a number of barriers on the luminal surface that may limit the efficiency of entry of most vectors. The complex tissue architecture of the organ also presents challenges to cell-based therapies not encountered in the bone marrow, for instance. That said, these disorders represent several of the most common single gene defects in North Americans and Northern Europeans and so will undoubtedly continue to garner much effort and attention.