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A gene transfer intervention for a rare inherited disease appears close to approval in Europe.

At press time, the European Commission (EC) was expected to approve alipogene tiparvovec, which would be marketed by Amsterdam-based UniQure as Glybera. If approved, Glybera would be the first clinically available gene therapy in the Western world. Gene transfer researchers say EC approval could boost the field's financing and reputation and help further the development of gene therapies for rare diseases affecting children, such as cystic fibrosis (CF) and severe combined immunodeficiency (SCID). Meanwhile, medical ethicists point to gene transfer's troubled past and raise questions about the quality of informed consent.

In July, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended approval of Glybera for use only in certain adult cases of ultra-rare familial lipoprotein lipase (LPL) deficiency involving severe or multiple pancreatitis attacks, despite a patient's dietary fat restrictions.

The disorder results from a defect in the gene that expresses LPL, an enzyme that breaks down fats. As a result, excessive fat particles accumulate in the blood, leading to potentially fatal pancreatitis attacks. Glybera is based on an adeno-associated viral (AAV) vector modified to carry an LPL gene that does not replicate. The therapy involves injecting a modified vector into a muscle, where it corrects the LPL and enables muscle cells to produce LPL.

“For the last decade, many have said gene therapy is coming. This, pending EMA approval, is a milestone toward having an actual gene therapy,” says Jeffrey Kahn, MD, PhD, MPH, Levi Professor of Bioethics and Public Policy and Deputy Director for Policy and Administration at Johns Hopkins University's Berman Institute of Bioethics in Baltimore, Maryland. Dr. Kahn is also a former member of the National Institutes of Health (NIH)-established Recombinant DNA Advisory Committee (RAC), which reviews most U.S. gene transfer research on humans. “Other therapies in the pipeline look promising, so someday physicians may have other clinical approaches using gene transfer technologies,” Dr. Kahn adds.

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Path to Approval

  1. Top of page
  2. Path to Approval
  3. Ethical Questions
  4. Informed Consent issues loom
  5. Pediatric research

Glybera “isn't a slam-dunk success,” says James Wilson, PhD, a Professor of Pathology and Laboratory Medicine at the University of Pennsylvania in Philadelphia, whose lab developed the vector used in the therapy. He points out that the EMA approval is narrower than what UniQure originally sought. Approval is based on data from only 27 patients and made “under exceptional circumstances,” meaning UniQure will need to set up a registry to monitor patient outcomes and provide ongoing data to EMA, Dr. Wilson says.

He notes that the data on which approval is based are not from the company's efficacy trial endpoint, which was reduction of triglycerides. Rather, approval is based on other data that show Glybera reduces pancreatitis episodes. Familial LPL deficiency's extreme rarity was also a factor, according to Monika Benstetter, a European Medicines Agency spokeswoman.

Dr. Wilson hopes that EC approval of UniQure will boost funding and interest in trials of gene transfer interventions, some of which have drawn controversy.

Ethical Questions

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  2. Path to Approval
  3. Ethical Questions
  4. Informed Consent issues loom
  5. Pediatric research

Debate surrounds gene transfer research because of high-profile deaths of a few people enrolled in trials. But prior to these tragedies, it was the possibility that somatic gene therapy could alter germline cells driving the controversy, says Ellen Wright Clayton, MD, JD, Director of Vanderbilt University's Center for Biomedical Ethics and Society in Nashville, Tennessee.

“That's a medical ethics question unique to gene therapy,” Dr. Clayton says, adding that the deaths—especially the highly publicized 1999 death of Jesse Gelsinger in a University of Pennsylvania trial of gene transfer for ornithine transcarbamylase (OTC) deficiency— raised questions about researchers' conflicts of interest, and whether the informed consent process adequately explained potential side effects.

NIH guidelines on informed consent for gene transfer research address these issues. They recommend that researchers not only reveal their conflicts of interest, but also make sure subjects understand the difference between research and treatment and are warned of possible unforeseen risks, especially if a therapy has been used in few or no humans.

The guidelines also recommend that researchers describe risks related to sexual activity. Subjects should be advised to abstain during and for some time after receiving gene therapy, the guidelines suggest. That's because viral vectors could shed, infect sexual partners, and present risk to their health and that of their future children.

Researchers should also discuss with subjects their participation in long-term follow-up, and any costs they could incur from research-related injury, the guidelines say.

RAC reviews all proposed gene transfer trials that are sponsored by, or will be conducted at, any institution receiving NIH funding for recombinant DNA research. While RAC is not an approval body, it makes recommendations about gene transfer trials that are conveyed to investigators by NIH. NIH then sends RAC's recommendations to bodies from which investigators need permission to proceed. These include the U.S. Food and Drug Administration (FDA), institutional review boards, and biosafety committees.

Informed Consent issues loom

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  2. Path to Approval
  3. Ethical Questions
  4. Informed Consent issues loom
  5. Pediatric research

RAC has a complicated set of criteria for considering research, including the investigators' explanation of how a vector will make a genetic change in the right place and affect the correct cells. Several criteria are related to the quality of informed consent, especially regarding subjects' understanding of risk.

“People recruited into these trials are likely to be very ill, without other therapeutic options, and many are desperate,” Dr. Kahn points out. RAC officials are concerned that subjects might overestimate benefits and underestimate risks. But often, a particular gene transfer has never been done before, so researchers do not even know all the risks, he adds.

Gene transfer research involving children is subject to federal regulations stipulating that research cannot impose greater than minimal risk to subjects who are children, unless there is a substantial likelihood of clinical benefit to them, Dr. Kahn notes.

Ethical breaches related to informed consent and the disclosure of researchers' financial interests that were discovered during the investigation of Gelsinger's death resulted in sanctions for researchers and changed FDA oversight of gene transfer studies. The FDA now requires researchers to submit plans for safety monitoring and does on-site inspections. The agency has also established a database for reporting adverse events.

Since Gelsinger's death, vectors have improved, along with knowledge about their risks, say Drs. Kahn and Wilson. Early vectors, including the one used in the OTC deficiency trial, were based on adenoviruses that induced immune response and inflammation, despite researchers' efforts to engineer ways to prevent them. Newer vectors, including the one used in Glybera, blunt the immune response.

Pediatric research

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  2. Path to Approval
  3. Ethical Questions
  4. Informed Consent issues loom
  5. Pediatric research

Meanwhile, some research with newer vectors addresses disorders uncovered by newborn screening, including SCID. St. Jude Children's Research Hospital in Memphis, Tennessee; the UCLA David Geffen School of Medicine Departments of Pathology and of Microbiology, Immunology, and Molecular Genetics; Boston Children's Hospital; Great Ormond Street Hospital for Children in the United Kingdom; and the NIH are among the institutions that have, or are now studying, gene transfers in SCID.

Previous research shows that leukemia is a risk of SCID gene transfer, says Nancy King, JD, Professor of Public Health Sciences and Codirector of the Center for Bioethics, Health and Society at Wake Forest University in Winston-Salem, North Carolina, and a former RAC member. SCID research is especially controversial. “Some say the risk is too great, while others say it's acceptable because if children get leukemia, it's treated with bone marrow transplant, which is what's done for SCID,” King notes. “There are a lot of ethical issues tangled up in that.”

CF is another active area of gene transfer research. In the U.K., a consortium of researchers from Oxford University, Imperial College London, and the University of Edinburgh has enrolled 130 CF patients, ages 12 and older, in a study in which they inhale a working copy of a healthy CF transmembrane conductance regulator (CFTR) gene via a specially engineered lipsome once a month for a year. The trial will assess whether the intervention improves people's lung function and reduces mucus, inflammation, and infections. A second study by the consortium will look at use of a modified virus to carry the replacement gene into the lungs.

A Glybera approval from the EC will give a needed boost to the gene transfer field and prompt more research that may someday benefit children with rare genetic diseases, Dr. Wilson predicts.

But Dr. Clayton is less sure. Serious side effects that didn't emerge from the small trial on which EC approval would be based might dampen enthusiasm for gene transfer research, she predicts. “But, if Glybera works without serious side effects, it will suggest a way forward.”