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Human Gene Therapy: Progress and Oversight

A Conversation With Carrie D. Wolinetz, PhD


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Carrie D. Wolinetz, PhD

Carrie D. Wolinetz, PhD

The early debate over the social and ethical implications of gene therapy led the National Institutes of Health (NIH) to establish the Recombinant DNA Advisory Committee in 1974. However, the risks of human gene therapies were largely unknown until 1999, when a patient died of a massive immune response during a gene therapy safety trial. Over the ensuing years, the U.S. Food and Drug Administration (FDA) and the NIH took steps to ensure the safety of gene therapy products. The ASCO Post recently spoke with Carrie D. Wolinetz, PhD, Associate Director of Science Policy at the NIH, about gene therapy oversight and related issues.

State of the Art

Gene therapy has, for good reason, elicited much excitement in the research and clinical worlds. What is the current state of gene therapy?

The really exciting research in this field has produced three FDA-approved gene therapy treatments. There are two chimeric antigen receptor (CAR) T-cell therapies, axicabtagene ciloleucel for the treatment of diffuse large B-cell lymphoma (DLBCL) and tisagenlecleucel for certain patients with DLBCL and young adults with acute lymphoblastic leukemia. The FDA also approved voretigene neparvovec-rzyl for patients who have an inherited retinal disease caused by mutations in both copies of the RPE65 gene and have enough remaining healthy cells in the retina.

There are many promising gene therapies still in the pipeline, including treatments for spinal muscular atrophy and hemophilia B, to name two of many. The FDA currently has more than 700 new investigational drug applications for gene therapies, so there’s a lot of exciting work going on.

Oversight System

Jesse Gelsinger was an 18-year-old boy with a rare metabolic disorder who entered a clinical trial for a novel form of gene therapy in September 1999. After receiving the therapy, Jesse experienced multiple organ failure and died. His tragic death led to greater scrutiny of this field. Please talk about the evolution of that scrutiny and where we are now.

I think our gene therapy oversight system is dynamic and rigorous enough to be able to judge areas where the risk is still unknown.
— Carrie D. Wolinetz, PhD

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Since the terrible events that led to Jesse Gelsinger’s death, there has been extensive strengthening of the oversight system. Also, the science involved in gene therapy has evolved, as has our knowledge about certain risks involved in this field. The FDA has clearly come a long way over the past few decades in terms of its ability to oversee gene therapy research. It’s become such a rich and diverse field over the years, and during that time, we have learned a lot about possible adverse events, especially in the clinical trial setting.

Since the death of patient Jesse Gelsinger, the NIH restored the Recombinant DNA Advisory Committee, which has played an important role in advising us on all issues concerning ongoing research in gene therapy. The Recombinant DNA Advisory Committee provides a transparent forum for discussing the complex issues surrounding the scientific, safety, and ethical concerns involved in gene therapy.

Given the current excitement about gene therapy, is there a concern that the rapid evolution in this field will outpace oversight?

I don’t think so, since oversight should always be commensurate with the risks involved. Our current oversight system is at a very good place to be able to gauge the risk equation in this field. To that end, we have a top-notch oversight system in place that includes institutional review boards and biosafety boards. Moreover, the FDA recently introduced cellular and gene therapy guidances that focus on these therapies when they enter the manufacturing sector, so there is a system in place to follow-up after they’ve penetrated the marketplace. I think our gene therapy oversight system is dynamic and rigorous enough to be able to judge areas where the risk is still unknown.

Ethical Issues

Have we fleshed out all the ethical concerns about gene therapy, such as germline gene therapy, when modified DNA is transferred into reproductive cells to correct inherited disease-causing gene variants?

So far, most of our interactions with researchers have been on the somatic side of this issue, gauging the risks of participants in clinical trials. Clearly the advent of newer gene-editing technologies has moved the concept of germline editing to the forefront of that approach. And there has been a lot of activity and discussion around this issue, but quite frankly, we’ve been evaluating this challenge for as long as we’ve had the ability to modify the genome.

The National Academy of Sciences gave a green light to the basic research arena but not yet to clinical germline modifications, because the underlying safety risks are still not adequately understood. Certainly from the NIH’s standpoint, we do not fund any gene editing in human embryos because the current benefit doesn’t outweigh the potential risk. And, of course, we have statutory limitations on our ability to use embryos in scientific research. There are many safety and ethical issues in germline editing that don’t exist in the somatic gene therapy arena.

Does CRISPR offer challenges similar to those associated with gene therapy, in terms of safety and ethical issues?

CRISPR is the “newest kid on the block,” but I don’t think this technology poses unique ethical issues. However, it is an example of a technology that has widened the field of acceptance and enabled some of these other applications like germline editing. There are still safety issues with CRISPR that have not been fully examined, particularly when it comes to in vivo editing of cells. So we have a ways to go in terms of safety before we can take the next step with CRISPR.

Closing Thoughts

Please share any last thoughts on this intriguing and provocative new technology.

At the NIH, we are particularly excited at the prospect of being able to cure life-threatening diseases using these sorts of approaches. NIH Director Francis S. Collins, MD, PhD, has boldly predicted that within the next 5 to 10 years, we could actually see a cure for sickle cell disease through a molecular approach. We’re focusing a lot of effort on that mission and believe we are on the brink of a transformative point for that particular disease, which will lead to more cures. It’s a very exciting time to be at the NIH. 

DISCLOSURE: Dr. Wolinetz reported no conflicts of interest.


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