Gene Therapy at Penn
Should Go Forward
But programs must meet the highest standards. By Judith Rodin

The September 17, 1999, death of a young gene-therapy volunteer named Jesse Gelsinger was a tragedy that we continue to mourn. It has left us resolved to redouble our efforts to run biomedical research programs that aim to save lives while upholding the highest possible standards for safety, accountability, conduct and informed consent.
    Unfortunately, a blizzard of sensational news stories has blurred fact with rumor, and threatened to smother the nascent but promising field of human gene therapy.
    As alumni and friends of Penn, you deserve to know what happened and what Penn has done to uncover all the facts surrounding this tragedy. As supporters of Penn, you should know the measures we are taking to uphold the highest ethical standards and to strengthen all phases of clinical research that relies on human volunteers. With the media frenzy unlikely to cool down anytime soon, I am using this column to answer your questions as well as I can.
    Researchers at the Institute for Human Gene Therapy (IHGT) were conducting a clinical trial to test the safety of delivering a potentially corrective gene to the livers of adult volunteers afflicted with ornithine transcarbamylase (OTC) deficiency, a rare genetic disorder that usually kills babies within days of their birth—although some do survive and are kept alive by a strict regimen of diet and medication.
    Jesse Gelsinger was one of 18 adult OTC patients who volunteered for the trial. Like his fellow volunteers, Jesse displayed a rare kind of selfless courage by agreeing to submit to a clinical trial whose purpose he knew was not to treat or cure his disease, but to determine whether the experimental gene transfer would prove harmful.
    Unlike any other human subject in this or any other clinical trial performed at the IHGT, Jesse suffered an extreme adverse reaction and died of multiple organ failure four days after receiving his initial intravenous infusion.
    We may never be able to pinpoint, with medical precision, the reason the gene transfer killed Jesse Gelsinger. However, we know that the IHGT team screened all volunteers, including Jesse Gelsinger, for eligibility before enrolling them in the OTC trial.
    We know our researchers informed all participants of the risks before obtaining their signed, written consent.
    We also know now that the IHGT team was neither 100 percent meticulous in its record-keeping nor 100 percent compliant in meeting each and every reporting requirement set forth by the federal Food and Drug Administration and by our own Institutional Review Board. But it is extremely important to recognize that none of these lapses appears to have had any connection to the tragic event of Gelsinger’s death.
    Nevertheless, this University cannot condone any lapse that creates confusion or raises doubts about Penn’s respect for the rights and welfare of others. We simply must hold ourselves to the highest possible standards for the conduct of research throughout Penn and render the highest possible level of cooperation and compliance with federal regulators.
    With this in mind, we had already begun taking a harder, critical look more than a year ago at our work with animal and human subjects across-the-board, in all schools, research centers and institutes at Penn, and in all our practices and procedures.
    In the aftermath of Jesse Gelsinger’s death, we have done still more:
I asked an independent committee of eminent scientists who have no affiliation with Penn to specifically investigate and assess the IHGT’s monitoring and oversight of all clinical trials, and offer their recommendations.
Already, the IHGT has taken aggressive measures to standardize its operating procedures, ensure full compliance with all regulations and promote precise, unambiguous and comprehensive communications with volunteers, IRB members and federal regulators.
The institute has added senior, experienced staff in toxicology and clinical trials, and it has established a high-level position for a chief operating officer who will have broad oversight responsibilities.
The IHGT has also engaged an outside contract research organization to monitor all clinical trials.
    Restoring the FDA’s confidence in the IHGT is critically important to this University’s mission to pursue cutting-edge biomedical research that can save lives. We must also demonstrate persuasively that private-industry sponsorship remains critical to clinical research, and that Penn should not abandon the field of gene therapy.
    Since the passage of the Bayh-Dole Act 20 years ago, the federal government has encouraged universities and industry to collaborate closely and productively to move the fruits of federally-funded research from the laboratory bench to the bedside and the marketplace. In the case of experimental gene therapy, to produce and test the vectors that deliver the corrective gene to patients would be prohibitively expensive without financial sponsorship from the private sector. The fruits of successful university research simply cannot adequately save lives without the support and business acumen that only private industry can provide.
    Is the field of gene therapy important?
    I believe it is. Gene therapy’s potential to find treatments and cures for cystic fibrosis, muscular dystrophy and other devastating genetic diseases is enormous. Recent headlines in The New York Times (“Hint of Success Indicated in Gene Therapy,” March 2) and the Wall Street Journal (“A Harmless Virus Shows Promise, May Revive Hopes for Gene Therapy,” March 29) demonstrate the great promise and fundamental scientific validity of gene therapy. At the Children’s Hospital of Philadelphia, scientists reported that two of the first three hemophilia patients treated with small quantities of corrective genes delivered by an adeno-associated virus showed signs of improvement.
    As all human gene-therapy trials move forward, researchers must proceed cautiously and do everything possible to minimize risk to volunteers. However, researchers in any cutting-edge medical field cannot eliminate risk completely. Testing the risk is one of the primary purposes of clinical trials. Had zero-risk been the threshold for proceeding with clinical trials involving human volunteers, medical science never would have produced vaccines for smallpox, diphtheria, polio and influenza. We never would have improved the management of heart disease or seen the introduction of increasingly effective treatments for AIDS and a wide range of cancers.
    As the proud home of the nation’s first medical school, Penn shoulders a historic responsibility to discover and develop the next generation of drugs, therapies and procedures to extend the frontiers of life. That is why human gene therapy experiments at Penn should go forward. But they will do so in a model program that will meet the highest standards for safety and accountability.
    Jesse Gelsinger was a pioneer who gave his life to a field that is only a decade old. When human gene therapy produces cures for genetic defects, the millions of saved lives will be Jesse’s enduring legacy.

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