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The risks of germline gene transfer. (another voice).

In this issue of the Report, Nancy King, a lawyer, bioethicist, and former member of the NIH Recombinant DNA Advisory Committee, highlights the broad array of ethical and societal issues raised by the risk of germline gene transfer of donated gene sequences--that is, the risk that the donated DNA sequences will be passed on to offspring of the recipient, with potential harmful effects. King's essay deals with the issues raised by the risks of inadvertent germline gene transfer, which she feels have not been adequately explored. She proposes that current strategies of gene transfer should be shelved and that researchers should rethink the entire approach and develop gene transfer strategies that are less likely to pose a risk of germline gene transfer.

King is right to raise these issues, and she is correct that they merit more attention than they have received. Especially important is analysis of exactly what it will mean to carry donated gene sequences in the germline. From the vantage point of the science, however, the problems alluded to by King take on a somewhat different cast.

How likely is this event to occur? Germline gene transfer has not been documented in the more than 4,000 human subjects that have been enrolled in gene transfer studies, although King is right that many of these subjects were probably not engaged in procreation anyway. In animal studies where inadvertent germline gene transfer has been carefully considered, (1) none has been found, although clearly more data are needed.

Tissue culture and animal experiments that measure the distribution in the body of the new genetic material shed some light on the probable risk for humans. King summarizes these studies by noting that "the stuff goes all over the place," but the vector is generally concentrated in the target tissue. In our studies of recombinant adeno-associated virus (AAV, a vector) injected into skeletal muscle or liver, the concentration of vector DNA in the gonads is 0.001 to 0.0001 of that found in skeletal muscle or liver. (2) These studies are mandatory before gene transfer can be attempted in humans.

Even after the vector has gained access to gonads, it must still gain entry to the eggs or spermatocytes for germline gene transfer to occur. The most stringent test for assessing entry is to incubate germ cells with vector and look for genetic transfer. These studies have been negative so far (using murine spermatogonia as the target for AAV), (3) but more studies are certainly needed.

Finally, even if foreign DNA gains access to a germ cell, in order for harm to result, it must lodge in a site where it can have an effect. Based on reasonable assumptions about the human genome and on data from a recent AAV trial, (4) the risk of detecting a birth defect caused by gene transfer appears to be less than one in one million--a negligible increase over the baseline risk of birth defects of about one in one hundred.

Where does all this leave us? In my judgment, the current approach of the regulatory agencies to this issue is the correct one. There are no licensed gene therapy products at this point, and most of the clinical trials under way are early phase studies that involve only small numbers of volunteer subjects. Given that the risk of inadvertent germline gene transfer is extremely low, that males at least can prevent deleterious consequences of this event by banking sperm prior to gene transfer, and that the goal of these studies is simply to determine whether efficacy can be achieved and the approach is worth pursuing, then the small risk involved would seem to justify the potential benefit to society of developing new approaches to a wide range of diseases. The regulatory agencies have also been quite clear that basic studies to identify vector receptors, and animal studies to assess the likelihood of germ cell transduction, must be pursued before larger scale trials are undertaken. King is absolutely correct that we need to begin to wrestle with the consequences of germline gene transfer now, but we must also stay grounded in science and the realities of drug development if we wish to develop novel therapeutics.

(1.) H.H. Roehl et al., "Analysis of Testes and Semen from Rabbits Treated by Intravenous Injection with a Retroviral Vector Encoding the Human Factor VIII Gene: No Evidence of Germ Line Transduction," Human Gene Therapy 11, no. 18 (2000), 2529-40.

(2.) M.A. Kay et al., "Safety and Efficacy Studies of AAV-Mediated, Liver-Directed Gene Transfer for Hemophilia B," Thrombosis and Haemostasis Suppl., 2001, Abstract #OC2491; V.R. Arruda et al., "Lack of Germline Transmission of Vector Sequences following Systemic Administration of Recombinant AAV-2 Vector in Males, Molecular Therapy 4, fro. 6 (2001), 586-92; also unpublished data.

(3.) Arruda, "Lack of Germline Transmission."

(4.) Department of Health and Human Services, National Institutes of Health Recombinant DNA Advisory Committee, minutes of meeting at Bethesda, Maryland, 11-12 March 1999; available at www4.od.nih.gov/oba/rac/minutes/3-99RAC.htm; C.S. Manno et al., "AAV-Mediated Factor IX Gene Transfer to Skeletal Muscle in Patients with Severe Hemophilia B," Blood, forthcoming.

Katherine A. High is William H. Bennett Professor of Pediatrics at the Children's Hospital of Philadelphia and an investigator at the Howard Hughes Medical Institute.
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Author:High, Katherine A.
Publication:The Hastings Center Report
Article Type:Column
Date:Mar 1, 2003
Words:885
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