A team of gene therapy researchers has reported positive results in a phase 1/2 clinical trial for the inherited bleeding disorder hemophilia B. A single intravenous infusion of a novel bioengineered gene therapy treatment enabled adult participants to safely produce sustained levels of clotting factor that prevented debilitating bleeding episodes. Patients were able to terminate prophylactic treatments--the gene therapy nearly universally eliminated their need for intravenous infusions of manufactured clotting factor.

"A one-time therapy sufficient to prevent bleeding without further medical intervention is the ideal treatment goal for patients with hemophilia," said lead investigator. "This cohort of 10 patients all safely experienced sustained clinical benefit after one infusion." The findings in the journal  New England Journal of Medicine.

The current trial's study team used a naturally occurring clotting factor that is hyperfunctional--eight to 10 times stronger than normal factor. Called Factor IX-Padua (FIX-Padua), it was discovered in an Italian family in 2009.

In the current study, the researchers used an adeno-associated viral vector to deliver their bioengineered payload of the gene that codes for FIX-Padua. Patients on the trial safely expressed that protein.

Hemophilia patients have an inherited gene mutation that impairs their ability to produce normal levels of a blood clotting factor, resulting in disabling or life-threatening bleeding, arising spontaneously or caused by trauma.

Hemophilia B, in which patients have low levels of clotting factor IX (FIX), has been used as a model disorder for the development of gene therapy research for more than two decades. The strategy of hemophilia gene therapy is to deliver a corrective gene into the patient with the goal of expressing therapeutic levels of blood clotting factor. Preclinical experiments in animal models of hemophilia successfully treated the disease, but human trials were frustrated by an immune response that defeated initial clinical benefits by inhibiting sustained expression of FIX.

Because higher doses of vector had previously stimulated this limiting immune response, the current researchers aimed for the lowest dose necessary to achieve clinical benefits--taking advantage of FIX-Padua's attributes.

Study patients maintained factor levels of approximately 33 percent, enough to move them out of the severe disease category and nearly eliminate all bleeding events. They were able to avoid the painful, disabling joint bleeds that previously occurred when their clotting levels dropped during typical fluctuations that occur with traditional treatment, consisting of regular doses of clotting factor. The researchers found the clinical benefits continued for up to 78 weeks of follow up.

None of the 10 patients had serious adverse events from the gene therapy. Eight of the 10 did not require external doses of factor, and nine of the 10 did not experience bleeds after the vector infusion. The only participant who had to administer factor already had significant baseline joint damage, but overall used 91 percent less factor than before the treatment.

http://www.chop.edu/news/one-dose-gene-therapy-produces-clotting-factor-safely-stops-bleeding-hemophilia-b-patients

http://www.nejm.org/doi/10.1056/NEJMoa1708538