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January 09, 2014

Advancing Gene Therapy

Streamlining development through data-sharing.

Advancing Gene Therapy

Creating and maintaining a database for sharing clinical data and research experience has proven a challenge. [© sparkstudio - Fotolia.com]

  • Unintended Consequences?

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    Scientist at work at the Core Manipulation Cell Facility at Dana-Farber Cancer Institute. [Photo by Sam Ogden, Dana-Farber Cancer Institute]

    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.

  • Data Leveraging

    Joy Cavagnaro, Ph.D., president of Access BIO, which specializes in preclinical pharmacology and toxicology studies, agrees that further development of gene therapy can gain much through data sharing. However, she prefers to apply “targeted” rather than “abbreviated” to studies enabled by data-based collaborations. “It’s more about leveraging data than having a standardized protocol,” she says.

    When Dr. Cavagnaro worked at FDA she was part of a team that helped formulate ICH guidelines on preclinical safety assessment for biotech products. That experience drove home the need to examine complex therapies case-by-case, rather than automatically adopting platform technologies.

    “There are many unknowns in gene therapy, and lots of questions to answer. You can’t have a standard study design,” she explains, regardless of how close protocols appear to be. She believes firmly in learning from previous studies, necessarily duplicating them exactly.

    The rub, given that FDA does not provide “competitor” data, is creating and maintaining a robust database for sharing clinical data and research experience. Several databases have cropped up, such as National Gene Vector Laboratory (NGVL), which was replaced by the National Gene Vector Biorepository and various offshoots. Then there is the Genetic Modification Clinical Research Information System (GeMCRIS), which provides access to information on gene transfer trials.

    The databases generally suffer from a lack of active participation, which is not surprising given the competitiveness of both academic and industrial developers of new therapies. Another issue is maintaining these resources, and making their data readily available.

    Dr. Cavagnaro notes another issue, related to the academic nature of gene therapy. “With small molecule drugs you pick a candidate and advance it into development. Maybe you have several backups as well, but you stick with the lead. In gene therapy the ‘product’ is a moving target. It’s constantly being tweaked.” That’s not necessarily bad, adds Dr. Cavagnaro. “Deciding to end research and begin product development is difficult, especially for academics.”

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