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“The Trials and Triumphs of Gene Therapy”
A talk by Inder Verma at Washington University School of Medicine
By Barbra Rodriguez

Advances in basic research are needed to bring gene therapy out of its infancy, but there are clear signs that the field is moving forward, said Inder Verma in a recent talk before researchers at Washington University School of Medicine in St. Louis. Verma directs the Laboratory of Genetics at the Salk Institute and is editor-in-chief of Molecular Therapy.

The promise of gene therapy, said Verma, is illustrated by the improved health of children born with severe combined immunodeficiency disease (SCID). French researchers treated a handful of these children using a retrovirus-derived vector containing a therapeutic gene needed to produce key chemicals required for immune cell development. Some of the patients have been free of severe infections for a year, according to an article in the December issue of Immunological Reviews.

Researchers also successfully treated a few hemophilia patients by using an adenovirus-associated vector to deliver a blood-clotting factor that is missing in the patients. Verma's lab and investigators at the University of Utah have independently used gene therapy to delay retinitis pigmentosa in mice. Baby mice in Verma’s study have gone 24 weeks with some healthy light-responsive eye cells, which normally deteriorate during the disease, producing blindness. "There's a possibility of restoring the ability of these mice to see," he said.

Verma, who has studied retroviruses for 15 years, now focuses on a modified form of the human immunodeficiency virus (HIV). The AIDS-causing virus and other lentiviruses can be used to infect non-dividing cells, which are more plentiful in the body. The ability to infect these cells expands the number of potential targets for gene therapy.

Verma's team removed the six disease-promoting genes of HIV and added other elements, such as a promoter that switches the virus' protein-producing ability from a trickle to a downpour in the absence of an antibiotic. The self-inactivating (SIN) lentivirus was injected into rat neurons and the animals produced an innocuous 'marker' protein on demand from the virus when an antibiotic was withdrawn from their drinking water. The researchers recently developed techniques for the large-scale production of the SIN vector, a necessary step before considering human clinical trials. The research was reported in the January issue of Molecular Therapy.

Verma noted that safety concerns about using viruses such as HIV need to be thoroughly investigated and better vector systems continually developed. He also stressed the need to overcome immune system rejection of virus vectors and of therapeutic genes themselves. Because of these concerns, he said, it will be important to consider therapy efforts involving hematopoeitic stem cells, the 'starter' cells of the blood and immune system that can be 'tricked' to develop into neurons and certain other cells.

Verma delivered his talk, "The Trials and Triumphs of Gene Therapy," on March 1, 2001 at Washington University School of Medicine.

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Fischer, A. et al. Gene therapy of severe combined immunodeficiencies. Immunol Rev, 178, 13-20 (December 2000).
Xu, K. et al. Generation of a stable cell line producing high-titer self-inactivating lentiviral vectors. Mol Ther 3, 97-104 (January 2001).

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