Hope for Hemophiliacs: Gene Therapy Can Stop the Bleeding

According to a research team, hemophilia will soon become the first well-known disease to be treated by a technique with record success


Hemophilia is a rare blood-clotting disease famously known for afflicting the royal families throughout Europe. One type, Hemophilia B, also called Christmas disease after Stephen Christmas, the first patient described with it, is caused by a defect in the eponymous gene on the X chromosome that leads to less than one percent of normal expression of Factor IX (FIX), an important blood clotting factor. Hence patients, who are usually male because they only have one X chromosome, require regular intravenous transfusions of Factor IX to prevent internal bleeding, or hemorrhage. These injections cost an individual patient about $300,000 a year, which may add up to around $20 million over a lifetime.

That may soon change due to a landmark study published this weekend in the New England Journal of Medicine. An international research team led by scientists at the University College London successfully used gene therapy (adeno-associated viral vectors) to replace the defective or missing copy of the FIX gene in a small cohort of patients, prompting the New York Times to write that Hemophilia B may be "the first well-known disease to appear treatable by gene therapy, a technique with a 20-year record of almost unbroken failure." The viral vector used by the team inserted the replacement gene into the liver cells of the hemophiliac patients, carefully avoiding the chromosomes to reduce the risk of inducing cancerous mutations, and induced physiologically relevant expression of the coagulation factor up to 22 months post-therapy. As the authors summarize in NEJM:

The development and widespread use of clotting factor concentrates for the treatment of hemophilia in the early 1970s dramatically improved the life expectancy for patients with the disease. Subsequent development of recombinant clotting factor concentrates has improved their safety profile, but there remains a strong interest in treatment strategies that would eliminate the need for long-term intravenous infusions and that would be available to the hemophilia population throughout the world. This study documents a critical step toward that goal and shows that sustained therapeutic expression of a transferred factor IX gene can be achieved in humans. The increase in FIX levels in our study participants was roughly dose-dependent, with the high dose of the vector scAAV2/8-LP1-hFIX (2×10^12 vg per kilogram) mediating peak expression at eight to 12 percent of normal levels. After peripheral-vein administration of scAAV2/8-LP1-hFIXco, four of the six participants were able to stop using prophylaxis with FIX concentrate without having spontaneous hemorrhage, even when they undertook activities that had provoked bleeding in the past. For the other two participants, the interval between prophylactic FIX concentrate injections was extended, but prophylaxis was not completely discontinued....

In summary, we have found that a single peripheral-vein infusion of our scAAV2/8-LP1-hFIXco vector consistently leads to long-term expression of the FIX transgene at therapeutic levels, without acute or long-lasting toxicity in patients with severe hemophilia B. Immune-mediated, AAV-capsid-induced elevations in aminotransferase levels remain a concern, but our data suggest that this process may be controlled by a short course of glucocorticoids, without loss of transgene expression. Follow-up of larger numbers of patients for longer periods of time is necessary to fully define the benefits and risks and to optimize dosing. However, this gene-therapy approach, even with the associated risk of transient hepatic dysfunction, has the potential to convert the severe bleeding phenotype into a mild form of the disease or to reverse it entirely.

This is a very exciting development not only for patients suffering from hemophilia, but for anyone with a genetic disease.

Image: Memitina/Shutterstock.

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