Gene Therapy

Edited by: Stephen P. Hoffert M.R. Knowles, K.W. Hohneker, Z. Zhou, J.C. Olson, T.L. Noah, P. Hu, M.W. Leigh, J.F. Engelhardt, L.J. Edwards, K.R. Jones, M. Grossman, J.M. Wilson, L.G. Johnson, R.C. Boucher, "A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis," New England Journal of Medicine, 333:823-31, 1995. (Cited in more than 100 papers through September 1997) Comments by Richard C. Boucher, University of North Carolina Cystic Fibrosis-Pulmonary Research and Treatment Center. The cystic fibrosis transmembrane regulator (CFTR) gene was isolated as the cause of cystic fibrosis (CF) in 1989. By 1993, gene therapy treatments for patients with CF began in earnest. While early studies reported some success with gene transfer, experimental flaws cast doubt on those results. In 1995, Richard C. Boucher, a professor of medicine at the University of North Carolina, Chapel Hill (UNC-CH), would publish a model clinical study for CF gene therapy (M.R. Knowles et al., New England Journal of Medicine, 333:823-31, 1995). GENE STANDARD: Richard Boucher directed a 1995 gene therapy clinical trial noted for its rigorous design. In this article, Boucher and his UNC-CH CF-Pulmonary Research and Treatment Center team showed that gene transfer using adenovirus vectors did not achieve therapeutic effects in CF patients. They demonstrated that increased doses of the vector brought on symptoms consistent with epithelial damage in two of three patients. Increased serum antibody activity, indicating an immunologic response to the vector, also was observed in a patient receiving the highest dose. This raised concerns that repeat treatments using an adenovirus vector would be unsafe and even less effective. Cystic fibrosis is the most frequent lethal genetic disease of childhood in the United States. Common symptoms include very salty tasting skin; persistent coughing and frequent pneumonia; excessive appetite but no weight gain; and bulky, foul-smelling stools. Most of these symptoms are attributed to the faulty transport of sodium and chloride within epithelial cells. CF patients often go on to develop pancreatic disease, liver disease, and lung disease. Advances in medicine have increased the median survival age from eight years old to 31 years old. But until the genetic cause of CF was isolated, physicians could only treat symptoms of the disease. One early study was notable for the use of adenovirus in delivering CFTR genes (J. Zabner et al., Cell, 75:207-16, 1993). Adenovirus is a DNA-containing virus causing respiratory illnesses and was then a widely touted vector. In the 1993 study, investigators reported improved nasal chloride transport in treated patients. Boucher's study represented a significant improvement over the 1993 study in that it involved more stringent research protocols. Under these rigorous controls, the 1993 results could not be duplicated, according to Boucher. "Unlike our work, the earlier study didn't use the patient as a control," Boucher explains. "By limiting the vector dosing to one nostril, we could use the other nostril as a control. We also blinded investigators to which nostril was treated when gene transfer was measured and used more reliable and sensitive devices for measuring the transfer. The discrepancies between the older study and our more rigorous study highlighted the need for standardized protocols in gene therapy research." Boucher also describes advantages gained from James M. Wilson's involvement on the project. Wilson, director of the Institute for Human Gene Therapy (IHGT) at the University of Pennsylvania, developed high-quality vectors that were known to be effective gene carriers. "Before, the quality and efficacy of vectors was not a given in experiments, but [IHGT] could provide those quality assurances. So, that was a major reason for the success of the study, and it is probably a major reason why people are citing the study."

Gene Therapy

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