HD Lighthouse Contributing Editor's Comment: The FDA shut down a clinical trial of gene therapy for arthritis. The study involved introducing a gene that blocks tumor necrosis factor which causes the inflammation leading to painful and crippling arthritis.

At this point, no one knows what, if anything, went wrong. The death could be a coincidence, or there could be a problem with the vector, or a problem with the way the gene was introduced to the patient, or there could be some other problem. The FDA will investigate and also review the 28 other studies currently using this vector. It was reported that there have been no other adverse events reported for trials similar to the clinical course the patient followed before his death although the details have not been given.

The Washington Post reports that the research had drawn a lot of scrutiny when it was first proposed in 2003. Reviewers wondered why this new and possibly risky approach would be tried with arthritis suffers, including some who had not yet tried existing treatments. They also noted that there was only a 'limited correlation' between the therapy and improvement in an animal model.

The Lighthouse will be following subsequent developments carefully. Gene therapy may also be helpful in Huntington's Disease, either in the form of RNA interferene with the HD gene or the introduction of a dominant gene which affects HD pathology, for example a gene for a neurotrophic factor.

The AAV (adeno-associated virus) vector developed by Targeted Genetics is the one used by Beverly Davison for her RNAi experiments. Targeted Genetics is now working with Dr. Davidson and SIRNA.

Gene transfer hold tremendous promise as a therapy for a variety of serious disorders, but there have been setbacks along the way and risks which were not anticipated.

In 1999, the gene therapy research community was rocked by the death of Jesse Gelsinger, a volunteer in a Phase I study where a gene for ornithine transcarbamylase was introduced to correct a rare genetic liver disorder. Jesse's disease was under control with medication but he wanted to help others, specifically children whose disease could not be controlled by medication. The adeno viral vector (not the same used by Targeted Genetics) caused a massive immune system reaction; without hours he was running a fever and had blood clots. He died of multiple organ failure four days later. An investigation found that although the consent form submitted to NIH for approval contained information about toxic reactions in monkeys, this information was removed from the form given to participants. Despite early indications of toxicity, the dosage was increased during the trial. Serious toxic reactions from two earlier patients were not reported to the FDA. Indeed, only 5 percent of adverse reactions in gene transfer studies going on at that time were actually being reported as required.

Since the Gelsinger case the FDA has been exerting greater oversight. Researchers are being more careful to follow approved protocols, and the vector has been further developed. The AAV vector developed by Targeted Genetics has been considered to be a safe one since over 600 patients have received it in a variety of trials.

Greater oversight and immediate reporting of adverse events increases the safety of these trials but any trial of a new treatment carries with it unknown risks. In 2002 and 2003, it was reported that three of nine children in France who had been cured of severe combined immunodeficiency disease (SCID) with gene therapy had developed cancer two to three years later. Children born with this disorder will die in the first year of life unless they can find a matching blood marrow donor, which is hard to do.

In two cases, the gene inserted itself just before another gene which, when activated, can cause leukemia. The cause of the cancer in the third case has recently been deduced from mouse studies. Salk Institute researchers followed the mouse model for a year and a half through their natural lifespan instead of the six months which is customary in the research. They found that one third of the mice developed lymphoma. "The bottom line here is that if you replace a gene that has multiple effects, you have to know more about its regulation and its ability to affect other genes and that requires extensive preclinical work and a much more careful analysis," said lead researcher Inder Verma, Ph.D., head of the genetics lab.

The SCID cases did not result in the kind of outcry heard with the Gelsinger case. Procedures had been followed and the children would have died without this intervention since no suitable donor had been found. The procedure is still being used on a case by case basis.

The SCID results, however, do illustrate an important point. Even where preclinical work has been done, preliminary results with people look good, and safety protocols have been carefully followed, there is still the potential of serious unanticipated side effects even years later. Participants in clinical trials need to educate themselves on potential risks, ask lots of questions, and weigh potential benefits against potential risks.

References:

Josephine Johnson and Francoise Baylis, "What Happened to Gene Therapy? A review of Recent Events," Clinical Researcher 14(January 2004):11-15.

Salk Institute Press Release, "Mouse study reveals human X-SCID gene therapy poses substantial cancer risk." April 26, 2006: http://www.salk.edu/news/news_press_details_20060426.php

Targeted Genetics Press Release: http://ir.targen.com/phoenix.zhtml?c=84981&p=irol-newsArticle&ID=1032343&highlight=

Rick Weiss, "Suspended Gene Therapy Test Had Drawn Early Questions," Washington Post Saturday, July 28, 2007; Page A09

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 31 Jul 2007

FDA Statement on Gene Therapy Clinical Trial

FDA

On July 24, 2007 the U.S. Food and Drug Administration (FDA) was informed by Targeted Genetics Corporation of Seattle about the death of a patient who received an investigational gene therapy product in a clinical trial for the treatment of active inflammatory arthritis.

FDA's condolences go to the patient's family.

FDA is providing this preliminary information in recognition of the public's interest in these types of new therapies.

Targeted Genetics notified FDA earlier that a patient in its trial experienced a serious adverse event. Even though the cause of the illness wasn't known, and is still uncertain, the agency immediately placed the trial on clinical hold--meaning no further product can be administered and no new patients can be enrolled.

The product that was being studied uses a particle called a vector that is designed to deliver treatment genes to target cells. The vector used is a recombinant adeno-associated virus (AAV) derived vector and delivers the gene for Tumor-Necrosis Factor -Receptor, with the intent to inhibit a key mediator of inflammation. In the study, the gene therapy was administered into the joint affected by the disease to reduce inflammation and disease in patients with active inflammatory arthritis.

More than 100 subjects have been enrolled in the trial, according to the company, without known similar serious events. However, the patient's illness was related in time to the receipt of a second injection of the product. Upon being alerted to the adverse event, FDA immediately began its investigation to determine whether the illness was related to the treatment. The investigation into the cause of the patient's illness and subsequent death is intensive and ongoing.

Targeted Genetics is cooperating with FDA's investigation and has agreed to provide the agency with ongoing results from various tests and all other information it is compiling that may help determine the cause of this patient's death. FDA is also coordinating with the National Institutes of Health in an effort to acquire a better understanding of the potential scientific and safety implications of this event. These matters will be discussed at the September meeting of the NIH Recombinant DNA Advisory Committee.

FDA is not aware of similar adverse events occurring in other gene therapy trials either with this specific product or with those that use other genes in AAV vectors. However, as a precaution, the agency is further reviewing all ongoing trials involving any use of AAV.

FDA recognizes the contributions of participants in clinical trials and places a high priority on potential safety issues – volunteers play a critical role in making treatments available that have the potential to help many other patients who need new treatments for serious diseases.

The agency is continuing to obtain and assess additional information to help determine, if possible, the cause of the event, and any potential implications and will take additional steps and provide updates as warranted.

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Source: FDA website

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