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Experts Debate Gene Therapy Vectors

Proponents of two divergent approaches to gene therapy engaged in a debate during the 34th Annual Meeting & Exposition of the Controlled Release Society (CRS) held July 7-11, 2007, in Long Beach, CA. John Chiorini, PhD, of the Gene Therapy and Therapeutics Branch of the National Institute of Dental and Craniofacial Research of the National Institutes of Health in Bethesda, Maryland, spoke in favor of using viral modes of gene therapy delivery. Leaf Huang, PhD, Chair of the Division of Molecular Pharmaceuticals in the School of Pharmacy at the University of North Carolina at Chapel Hill, countered with an argument for nonviral methods of delivering genetic material. The purpose of the CRS annual meeting is to deliver knowledge and service by advancing science, technology and education in the field of controlled delivery of bioactive substances.

In support of his position, Chiorini explained to attendees that viruses are well suited as delivery vehicles, also called vectors, because they can effectively introduce nucleic acid into a host’s cells. Modified viral vectors can be used to transfer genetic material that is well tolerated by the recipient. Chiorini mentioned other necessary characteristics of a suitable vector, including stability, efficiency, targeting, controllability, long-term expression, alterability and ease of manufacture.

Huang led his counterpoint by asserting a commonly cited drawback to viral vectors—their safety record. He stated that in every gene therapy clinical trial-related death to date, a viral vector was the cause. The use of certain vectors also carries a risk of adverse cellular reactions that could cause cancer.

"The biggest advantage of nonviral systems is that they are nontoxic," said Huang. "Even the safest viral vectors, like adeno-associated viral vectors and lentiviral vectors, are still immunogenic."

Chiorini responded to the safety question, specifically to trials in France where some children undergoing gene therapy for x-severe combined immunodeficiency syndrome had developed leukemia. He explained that only a small number of those gene therapy subjects were affected. Once the problems were discovered, he explained, trial designs were adjusted and no further cases have since been reported.

Huang added that targeting ability and flexibility are some other advantages of nonviral vectors. He gave two examples to support his argument—hydrodynamic injection of naked DNA (DNA not surrounded by the virus’ outer protein envelope) and mechanical massage, both of which have shown prolonged high levels of gene expression when tested in mice.

The debate shifted back to efficiency. Although the use of nonviral vectors means that greater volumes of DNA must be injected, Huang had no reservations, as long as the doses remain inexpensive and nontoxic. Chiorini countered, saying that the use of higher volumes increases the chances of an immune response in the patient. He added that the peptides (chains of amino acids linked together) in nonviral vectors are in some manner immunogenic and therefore raise the risk of an unwanted immune reaction even further. "Less is better in this case," he said.

The debate concluded with both Chiorini and Huang admitting that his opponent had made valid points and that each does, in fact, work to some degree employing the other vector. According to CRS, the session ended on a "light-hearted note with the debate having generated significant discussion and involvement from the assembled audience."

Source: BioPharma Reporter (online) July 18, 2007


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