David A. Williams, M.D., chief, division of hematology/oncology at Children's Hospital Boston and director of the gene therapy program at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, was part of an international team to develop a safer vector for SCID-X1 treatment. Dr. Williams presented an interim analysis of a clinical study using the improved gamma-retrovirus vector at the ASH conference in New Orleans last fall.
One of Dr. Williams’ research interests involves the predictive ability of mouse models for human gene therapy clinical trials. “FDA requires many of these expensive, time-consuming studies,” he says. “The question is whether they are reliably predictive. One could question whether it makes sense require those studies at all. FDA is itself questioning this.”
Dr. Williams is “as sure as one can be” that the leukemia cases in SCID-X1 arose from the viral vectors, in which the replacement gene was expressed in a region known as the long terminal repeat, which contained a potent enhancer as well as the promoter. “Because of this very strong enhancer, genes close to the insertion site were expressed even when they should not have been. The enhancer overrode the endogenous regulatory sequences of the human gene,” explains Dr. Williams.
Moreover, the time it took for leukemia to develop, around three years, pointed to an initial event which, while not by itself responsible for leukemia, induced additional genetic abnormalities that led to the illness.
Dr. Williams’ team redesigned the vector to eliminate the implicated sequence. “It sounds simple, but we had to redesign several characteristics of the vector, including how the correcting gene was expressed,” he says. Since the sequence was relevant to how the virus was manufactured, the production method had to change as well.
Will future trials in gene therapy always be haunted by the specter of unintended consequences? “Yes and no,” Dr. Williams says.
In the initial SCID-X1 trial the mouse virus used to make the vector causes leukemia in mice, but since the implicated genes were removed—and the insertion rate not very high— researchers did not expect the rate of leukemia that they observed. “In retrospect, it’s easy to say everyone should have expected this, but at the time it was believed unlikely that we would observe leukemia-transforming events,” continues Dr. Williams.
Still, he notes, mouse studies may not predict side effects in humans. “The only way to know is through human testing.” Ethical considerations are complex for such studies, but in the case of many pediatric genetic diseases the alternative to treatment is often the death of the patient. “The standard for Phase I trials moving forward is at least some possibility of improvement,” he points out.