March 29, 1999

Mice Cured Of Hemophilia By Salk Gene Therapy Protocol

Salk News

Mice Cured Of Hemophilia By Salk Gene Therapy Protocol

La Jolla, CA – With the aid of a common virus used to ferry a clotting factor gene into liver cells, a team led by researchers at The Salk Institute for Biological Studies has cured a form of hemophilia in mice.

The results demonstrate the potential for curing this and similar bleeding disorders in humans. These debilitating genetic ailments can exact health care costs totaling millions of dollars during an inflicted person’s life.

“A single injection of the modified virus, called a vector, cured the mice for five months, a quarter of their life span,” said Inder Verma, Salk professor and lead author of the study, published in the current issue of the Proceedings of the National Academy of Sciences. “If the same could be achieved in people, it would be like curing a hemophiliac for 20 years with a single shot.”

As described in their study, the investigators employed a genetically engineered version of adeno-associated virus (AAV), a small non-pathogenic virus to which a large proportion of the U.S. population has been exposed. They inserted into the vector the clotting factor IX gene, the blueprint for a protein defective in people afflicted by hemophilia B.

“Mice that received the vector treatment produced as much, and in some cases more, clotting factor than normal mice,” according to Lili Wang, Salk postdoctoral researcher and first author of the study. “The level of factor was about five to ten times that achieved in previous studies.”

The investigators believe the reason for the boosted levels is the specific “promotor” included on the vector, a segment of DNA that drives gene activity. The promotor, called LPS, is active in the liver, the body’s natural production factory for clotting factor. The vector was targeted to the liver through modifications to its external coat, the part of a virus that recognizes and clings to the cells it infects.

“Basically, we optimized every possible angle for gene activity,” said Verma. “We sent the gene to its natural home in the body and put it under control of a potent accelerator.”

Results of the study demonstrated the success of the introduced clotting factor. Unlike their litter mates, mice that received gene therapy did not experience spontaneous internal bleeding, and they recovered from scratches and cuts as well as ordinary mice. “This is one of the first examples of a complete cure of a genetic disease through a gene therapy approach,” said Verma.

The new vector will not be appropriate for all applications, however. For example, hemophilia A, which exacts an even greater societal cost in the U.S., is caused by a defect in the clotting factor VIII gene, and that gene is too bulky to be added to the petite AAV-based vector. Other vectors under development in the Verma laboratory, some based on stripped-down versions of HIV, should be able to accommodate larger genes.

“Ultimately, gene therapy vectors and protocols will probably be tailored to suit individual situations,” explained Verma. “But the current picture is extremely encouraging in that we are seeing proof of principle that gene therapy can effect a complete cure.”

Both AAV and HIV-based vectors surmounted obstacles previously facing the gene therapy field-they can deliver genes to non-dividing cells, which represent the majority of the body’s cells, and do so without prompting an immune response.

Additional Salk co-author is postdoctoral researcher Kazuaki Takabe. The study, titled “Sustained correction of bleeding disorder in hemophilia B mice by gene therapy,” was conducted in collaboration with Scott M. Bidlingmaier and Charles R. Ill at the Immune Response Corporation in Carlsbad, Calif. The work was supported by the March of Dimes Birth Defects Foundation, the H.N. and Frances C. Berger Foundation, the Wayne and Gladys Valley Foundation and the National Institutes of Health. Verma is an American Cancer Society Professor of Molecular Biology.

The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.

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