Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Some scientists argue that gene therapy is overregulated.

Last August, the Institute of Medicine (IOM) Committee on the Independent Review and Assessment of the Activities of the NIH Recombinant DNA Advisory Committee (RAC) found “sufficient reason for the RAC to continue, albeit in a restricted role.”

The RAC is a federal advisory committee that provides recommendations to the NIH Director related to basic and clinical research involving recombinant or synthetic nucleic acid molecules. It was formed in 1974 by the NIH in response to concerns about gene transfer into humans to provide oversight and a public forum for discussion. To date, NIH-supported researchers are still required to submit all research protocols to the RAC, which then determines which of these require further review and public discussion by the RAC.

But, as experience with gene therapy has grown, including accumulation of safety data and increased experience with its applications, gene transfer research’s associated risks are now better understood, and many interested parties, including scientists, have argued that today RAC review is “redundant and unnecessary” in its current form.

Gene therapists have lodged their own complaints about the RAC, arguing in 2012 that their clinical trials should no longer have to undergo a review by a special federal advisory committee. Hence, the “fresh look” at the role of the RAC.

“Gene therapy is overregulated to the point where it’s crippling progress,” maintains Xandra Breakefield of Massachusetts General Hospital in Charlestown, president-elect of the American Society of Gene and Cell Therapy (ASGCT).

The ASGCT says that the two potential issues with gene therapy that worried people most, altering germline DNA or creating a new pathogenic vector, “haven't materialized for the vectors that most trials now use.” In a letter to the RAC that Breakefield read at a RAC meeting, the ASGCT believed that instead of reviewing individual protocols, RAC should instead focus on “new areas of research. The overarching goal of the IOM was to ensure patient safety and the ethical conduct of research, while not subjecting scientists to unnecessary regulatory burdens, which can impede or delay scientific exploration and medical innovation.”

But it could be argued that historically safeguards for patients, institutional or otherwise, did not work well as they could have as investigators got caught up in the possibilities of creating a new gene therapy paradigm. The field has been haunted by the death in 1999 of Jesse Gelsinger, a patient enrolled in a gene therapy trial at the University of Pennsylvania’s Institute for Gene Therapy.

“With what I know now, I wouldn’t have proceeded with the study,” said James M. Wilson, M.D., Ph.D., the medical geneticist who headed the study, during an interview with Scientific American in 2009. In the 1990s scientists such as himself, he explained, were caught up in the promise of gene therapy, and didn’t realize that they did not know enough to warrant human testing. “We were drawn into the simplicity of the concept. You just put the gene in.”

He and his colleagues sought to test the safety of a gene therapy for ornithine transcarbamylase (OTC) deficiency, a disorder in which the liver lacks a functional copy of the OTC gene, thereby preventing the body from eliminating ammonia, a toxic breakdown product of protein metabolism. The Penn scientists had engineered an adenovirus to deliver a normal copy of the OTC gene into the liver. Seventeen patients had undergone the treatment before Gelsinger, who was in the cohort receiving the highest dose of the therapy.

Gelsinger died, having suffered a massive immune response triggered by the use of the adenoviral vector used to deliver the gene into his cells, leading to multiple organ failure and brain death.


What Went Wrong?

In trying to understand what went wrong in this patient’s case in the years since the study, Dr. Wilson and his colleagues hypothesized that protein components of the vector capsid required for the vector to function “inadvertently trigger antigen presenting cells to elaborate inflammatory cytokines.” Unfortunately, he noted, “modifications of the vector genome will not and apparently did not circumvent these innate immune responses.”

Dr. Wilson’s study was not the only poster child for unforeseen events in gene therapy trials. Efforts to find an alternative therapy to allogeneic hematopoietic stem cell transplantation to treat X-linked severe combined immune deficiency disorder (SCID) resulted in one of the first great success stories for gene therapy. Alain Fischer’s group at the Institut National de la Santé et de la Recherche Médicale in Paris successfully treated children with X-linked SCID with genes delivered using retroviral vectors. But two and a half years after treatment, one of the patients involved in the Fischer trial developed what was most likely acute T-cell leukemia. Additionally, the patient’s cells appeared to be monoclonal and overexpressing a potential oncogene found at the site of retroviral insertion.

But two articles published in Science Translational Medicine in 2011 revitalized hopes for gene therapy, as long-term survival data among 14 of 16 children treated with gene therapy for SCID showed that gene therapy without myelosuppressive conditioning effectively restored T-cell immunity and was associated with high survival rates for up to nine years. As of 2011, one child who developed leukemia during gene therapy remained in remission.

Gene therapy’s comeback is also fueled in part by the European Medicines Agency 2012 marketing approval of Dutch biotech company uniQure’s Glybera® (alipogene tiparvovec) for commercialization in the European Union. The product, based on an adeno-associated virus (AAV) gene vector, was developed to treat lipoprotein lipase deficiency (LPLD), a rare inherited condition that is associated with increased levels of fat in the blood caused by alterations in the gene that codes for the enzyme lipoprotein lipase.

Investors in the company will not only be buying into Glybera, but also into four other gene therapy products approved to enter clinical trials in the next nine months, including a treatment for hemophilia B in which the gene for the blood-clotting protein Factor IX will be delivered into patients’ liver cells; a therapy for acute intermittent porphyria, in which uniQure will use its adeno-associated viral vector to deliver correct copies of the gene coding for porphobilinogen-deaminase, an enzyme involved in the production of heme and a treatment for Parkinson’s disease.

Glybera has been tested in three clinical studies conducted in the Netherlands and Canada, in which a total of 27 LPLD patients participated. One follow-up study is still ongoing. In all three clinical trials, Glybera was well tolerated, according to the company which says “no relevant safety signals were detected.”

Last week, Bluebird Bio, a clinical-stage firm developing gene therapies for severe genetic and orphan diseases, announced that the company and its clinical investigator will provide an oral presentation on its HGB-205 study in beta-thalassemia major patients at the 19th Annual Congress of the European Hematology Association in Milan next month. Bluebird’s gene delivery technology is based on lentiviral vectors for gene delivery and the presentation will discuss “outcomes of gene therapy for beta-thalassemia major via transplantation of autologous hematopoietic stem cells transduced ex vivo with a lentiviral beta globin vector.”

As part of the IOM review of the RAC, the position paper written by the regulatory committee of the Alliance for Regenerative Medicine (ARM), in conjunction with ARM’s Gene Therapy and Gene-Modified Cell Therapy Section, acknowledged that historically, the RAC has served an important function. The Committee “encouraged evolution of the regulatory process for evaluation of gene therapy clinical trials and envisions a streamlined role for the RAC,” recommending creation of a risk-based approach to determine whether RAC review was needed.

On May 22, NIH Director Francis S. Collins, M.D., Ph.D., issued a statement accepting the IOM’s recommendations regarding the RAC review of gene therapy research from oversight and review of clinical gene transfer protocols: Assessing the role of the RAC, Dr. Collins stated that the NIH will now follow the IOM’s criteria to minimize the number of gene transfer protocols that are reviewed by the RAC. This means that “certain protocols that meet the IOM’s criteria for additional oversight may still be selected by the NIH Director for public RAC review.”

The NIH will issue a proposed update to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, which will be made available for public comment. Given the multiple complexities associated with gene therapy, its difficult clinical trial history, its potential in treating grave human diseases, and increasing numbers of gene therapy clinical trials, it’s a good thing the RAC will be around, “streamlined” role notwithstanding.









































Patricia Fitzpatrick Dimond, Ph.D. (pdimond@genengnews.com), is technical editor at Genetic Engineering & Biotechnology News.

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