WASHINGTON _ The Recombinant DNA Advisory Committee(RAC) to the National Institutes of Health on Thursday approved thefirst protocol for human gene therapy aimed at mitigating rheumatoidarthritis, by a vote of 13 to 0, with one abstention. This is also the firstprotocol aimed at a chronic rather than deadly condition.Rheumatoid arthritis destroys the tissues of joints. It typically afflicts 1percent of the population, rising to 5 percent of women over 65. It isincurable, and 10 percent of sufferers become disabled. For many, theonly recourse is prosthesis.Interleukin-1 is a major link in the chain of reactions that causes theinflammation and joint destruction that accompanies rheumatoidarthritis. The Phase I protocol will be carried out by principleinvestigator Christopher H. Evans, of the University of Pittsburgh, onabout six patients who are scheduled to have prosthetic knucklesimplanted. Prior to the operations, the researchers will remove cellsfrom the disabled joints, transduce them with the gene for theinterleukin-1 receptor antagonist protein (IRAP), and return the cells tothe joint. The safety of the protocol will be ensured by the removal ofthe material during surgery for prosthesis.Preliminary data from studies conducted on rabbit knees suggested thatthe IRAP gene product inhibits development of antigen-inducedarthritis. Human studies using the gene against asthma, psoriasis, andother maladies have demonstrated safety.The committee's major objection to the protocol was use of the genefor thymidine kinase (TK) to render the transduced cells sensitive togancyclovir, an anti-herpes drug, so that they could be killed if thegene proved damaging. "Some patients don't tolerate this drug," saidRAC member Stephen Straus, chief of the laboratory of clinicalinvestigation, National Institute of Allergy and Infectious Diseases.The motion to approve the protocol specified that the TK gene mustnot be used.That suited the investigators. "It will mean we won't have anyproblems with giving these patients an antiviral," Evans said.The university licensed patents related to the technique to TheragenInc., of Princeton, N.J., Evans told BioWorld. But that company isabout to merge with GenVec Inc., of Rockville, Md., and "it's unclearwhat their position is on arthritis."Also approved, 10 to 4, was a protocol for a gene therapy vaccineagainst metastatic colon cancer, which is being developed by David T.Curiel, director of the gene therapy program, University of Alabama,Birmingham. However, the magnitude of opposition was so great thatNIH director Harold Varmus may not be able to approve it, RACchairman LeRoy Walters told BioWorld.In this experiment, researchers plan to inject into the deltoid muscles of15 human subjects the naked DNA for an antigen which is expressedon colon cancer cells, called carcinoembryonic antigen (CEA). Aplasmid would serve as vector.Members questioned why the human immune system should respond tothe CEA in the muscle when it had failed to respond to this antigen onthe cancer cells. The preclinical studies offered poor support for theprotocol because they had used only animals that had never beenexposed to the antigen.Responding to this criticism, Robert Zaugg, vice president of businessdevelopment at Vical, Inc., of San Diego, which developed thevaccination strategy told BioWorld that it is particularly powerfulbecause, unlike conventional vaccines, the protein would besynthesized continuously inside the cell.Despite the concerns about the preclinical studies, it was approvedbased on the safety of the protocol and the potential importance of thetechnology. n
-- David Holzman Special To BioWorld Today
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