© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 10, 829-830,
May 19, 1999
© 1999 Oxford University Press
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In Utero Gene Therapy Is Still a Distant Promise
Undaunted by gene therapy's limited treatment success so far, W. French Anderson., M.D., at the University of Southern California's Norris Comprehensive Cancer Center, is still dazzled by its potential — especially for treating genetic diseases.
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But Anderson, one of the technique's pioneers, says it will be at least 3 years before the first in utero gene therapy is attempted.
Speaking at a recent tribute to R. Michael Blaese, M.D., who retired after 33 years at the National Institutes of Health (see News, Aug. 19, 1998), Anderson said that there are a number of technical hurdles investigators need to overcome before attempting to correct a genetic defect in the fetus. These include designing vectors with regulatory sequences that do not induce immunity and site specific integration — or getting transduced genes where investigators want them to go.
Undercut Benefits
According to Anderson, both these problems have undercut gene therapy's potential benefit to the more than 3,000 patients worldwide who have received gene-engineered cells so far. "No one has really been helped yet," he contended. "Either there are not enough cells with the therapeutic gene . . . or the genes shut down even where we get a therapeutic gene in."
In early discussions or "preproposals" for in utero gene therapy, two diseases have been put on the table before the Recombinant DNA Advisory Committee, which advises National Institutes of Health Director Harold Varmus, M.D. (see News, Oct. 21, 1998). These are adenosine deaminase (ADA) deficiency, a crippling immune disorder and the first disease ever treated with gene therapy, and alpha thalassemia, a blood disorder that often causes prenatal death.
But Anderson said that alpha thalassemia already has been ruled out as a viable candidate because the risk of a partial correction is unacceptable. "This is a major criticism [of this study]," he said, "and one that we ourselves pointed out." Instead, investigators will wait and see if they can successfully treat the rare fetus who survives to term with this disorder, he said.
In the meantime, there are a host of other diseases under discussion for an initial in utero gene therapy attempt: neurologic/metabolic disorders such as Tay-Sachs disease and Lesch-Nyhan syndrome; Fanconi's syndrome, another hematologic disorder; and the immune deficiency disease, Wiskott-Aldrich syndrome. While some patients may benefit from bone marrow transplants, Anderson said, all of these diseases are caused before birth and in utero gene therapy is "the only way to treat them."
One ethical concern that has dominated the RAC debate so far is whether in utero gene therapy will inadvertently alter germline cells in a fetus, which is outlawed under federal regulations. Anderson said that even though this is a possibility, a number of laboratory experiments have demonstrated "that it is impossible to get into the germline after the first trimester." If this continues to prove true, he added, then "the danger may not be what we thought earlier . . . and the germline issue may not be an issue."
Other Reasons
There are additional reasons for avoiding in utero therapy during the first trimester of pregnancy, according to Anderson. Not only is fetal size too precarious at this time, but the technical procedures do not exist, he said. Moreover, from sheep studies, investigators now know that the first week of the second trimester is the "only time in our lives when we have huge numbers of circulating stem cells" — making it an ideal time for targeting potentially therapeutic genes.
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