Gene therapy delivered to muscle was able to completely correct hemophilia B deficient blood clotting in a safe and well-tolerated manner for several years — in animal models of the condition.
The study with finding, “Complete correction of hemophilia B phenotype by FIX-Padua skeletal muscle gene therapy in an inhibitor-prone dog model,” was published in the journal Blood Advances.
Gene therapy holds promise for the treatment of hemophilia B, whereby a normal gene of the blood clotting factor IX (FIX) gene, which is deficient in this type of hemophilia, is delivered to the liver.
Clinical trials testing uniQure’s AMT-061 investigative therapy, and SPK-9001 developed by Pfizer and Spark Therapeutics, have shown that an adeno-associated virus (AAV) viral vector targeted to the liver can induce the expression of functional FIX and prevent bleeding episodes for long periods in patients with hemophilia B.
However, there are important safety risks associated with these liver-targeted therapies, because some patients start to develop an immune response against the AAV viral vector.
Moreover, some patients are ineligible for this type of therapy, including those with viral hepatitis derived from contaminated blood products.
So, researchers set out to investigate if gene therapy could be delivered through the muscle. They used two dog models of hemophilia B, which received a therapy containing an AAV vector enclosing a canine FIX gene, called FIX-Padua, with high-activity levels.
The therapy was administered as a single injection in the muscle of one of the limbs and led to a progressive increase in FIX levels in the blood, that stabilized between 54% to 85% of the normal levels, 150 days following administration. This was accompanied by a seven- to 10-fold increase in the activity of FIX.
Importantly, both dogs did not experience any bleeding event in the six-year follow-up after being treated.
The therapy was safe, not inducing any adverse effects, including abnormal activation of blood clotting or thrombosis (formation of blood clots).
Moreover, treatment was well-tolerated with no detectable immune response against the FIX-Padua protein, even after more than two years without immunosuppressive treatments.
This positive response to therapy was observed in dogs with a type of FIX mutation that makes them the most difficult to treat animal model of hemophilia B, which previous gene therapy attempts have been unable to treat.
“A comprehensive evaluation showed no immune response to FIX-Padua in a highly provocative scenario, combining the most challenging animal model with a target tissue that is not predisposed to immune tolerance,” researchers wrote.
In addition, in a more amenable dog model, immune tolerance to the therapy was proven even eight years after its administration.
“Combined, these data narrow the gap between liver and skeletal muscle AAV gene therapy, in terms of efficacy, by demonstrating long-term expression of curative levels of FIX-Padua, and in terms of safety, because there is no increased immunogenicity upon challenges.”
The team added that the delivery method already has been proven safe in subjects with muscular dystrophy receiving saline alone and would be anticipated to have a safer profile in hemophilia B subjects with healthy muscle tissue.
Together, these results form the basis for studies of muscle-directed expression of FIX-Padua in patients with liver diseases and with a broad range of underlying FIX mutations, researchers concluded.