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Gene therapy benefited patients with severe hemophilia B

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53rd ASH Annual Meeting

SAN DIEGO — A single peripheral-vein infusion of a modified adenovirus-associated serotype 8 vector expressing a Factor IX transgene consistently led to long-term expression of the transgene in six patients with severe hemophilia B, according to the results of a study published online in The New England Journal of Medicine and also presented here.

“We have favored [adenovirus-associated virus] for a variety of reasons, including that — despite the fact that it is endemic in humans — it does not apparently cause disease in humans,” said study researcher Andrew M. Davidoff, MD, chairman of the Department of Surgery at St. Jude Children’s Research Hospital in Memphis, Tenn. “In addition, it has a great tropism of propensity for infecting the liver, which is the site of Factor IX synthesis and the desired target of our gene transfer.”

Six men with severe hemophilia B (Factor IX activity, <1% of normal values) were enrolled in the study after meeting entry criteria and not possessing neutralizing antibodies to serotype 8, as determined by an in vivo transduction-inhibition assay. All except one participant received regular prophylaxis with Factor IX concentrates two or three times per week before gene transfer. Participants were divided into one of three groups and selected to receive a high-, intermediate- or low-dose of vector, which was administered without immunosuppressive therapy.

After an observation period of 6 to 16 months, adenovirus-associated virus-mediated expression of Factor IX between 2% and 11% of normal levels was observed in all participants. Four of the six discontinued Factor IX prophylaxis and remained free of spontaneous hemorrhage. In the other two patients, the interval between prophylactic injections was increased.

According to researchers, peripheral-vein infusion of serotype-8–pseudotyped, self-complementary adenovirus-associated virus vector expressing a codon-optimized human Factor IX transgene was well tolerated by patients. Furthermore, peripheral-vein infusion also led to long-term expression of the Factor IX transgene at therapeutic levels, without acute or long-lasting toxicity.

“We have demonstrated with two methods, measuring Factor IX activity and clinically dispensing with the need for prophylaxis in at least two-thirds of the patients, that this is an efficacious approach,” Davidoff said. “We do remain vigilant and concerned about the issue of T cell-mediated immunity to transduced hepatocytes and will continue to monitor this in future subjects, as well as try understand the mechanism and whether certain patients, for whatever reason, might be predisposed to this.”

Disclosure: The researchers report a financial relationship with Amsterdam Molecular Therapeutics.

For more information:

• Nathwani A. Abstract #543. Presented at: 53rd Annual Meeting of the American Society of Hematology; Dec. 10-13, 2011; San Diego.

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