a better-functioning gene that allows patients to produce the clotting factor on their own, a much more lasting solution, would dramatically shift the treatment landscape. That’s why the field has crowded with a bunch of hopefuls developing gene therapy treatments. Among them: Dimension (though a deal with Bayer), Baxter International, and Pfizer (via a partnership with Spark).
What sets Biogen from many of those competitors in the case of hemophilia is its choice of vector. Most gene therapy hopefuls are using adeno-associated viruses (AAVs) as their vectors in these programs. These tiny viruses, which don’t cause disease in humans, are relatively easy to manufacture, and have been shown in a large number of studies so far to be safe. Dimension/Bayer, Baxter, and Spark/Pfizer are all using AAVs in their hemophilia programs.
In this collaboration, however, Biogen is turning to lentiviruses—the family that includes HIV—which are modified so that they can no longer cause disease. Lentiviruses are larger than AAVs, can deliver larger amounts of genetic material into a cell, and integrate into a cell’s genome. Bluebird, for instance, is using lentiviruses for a gene therapy it’s developing for beta-thalassemia and sickle cell disease.
“[With lentivirus], every cell that’s made afterwards has that fix,” Bluebird CEO Nick Leschly explained to me recently. “Whereas AAV…just sits there and produces your protein, but if it dies, it dies.”
[Updated with Danos’ comments] Indeed, Danos noted that a lentivirus approach might have a more lasting effect in children with hemophilia because with an AAV, young patients could see “diminishing returns over time” as their livers grow and “dilute the signal.”
“This is not expected to happen with lentivirus,” Danos said. “This is what’s being seen in the preclinical data that [TIGET] has.”
That advantage would be mitigated if any safety issues crop up and the newly introduced genes create any other problems. Danos said the risk of such an event is low, but Biogen will keep a close eye on that as it digs through TIGET’s preclinical data.
Williams told Xconomy recently that Biogen was looking at both AAV and lentivirus, and that it would depend on the situation which vector it’d go for. “We’re sort of agnostic on platform, it’s driven by therapeutic area,” he said at the time. “Right now, for hemophilia, there’s a lot of activity…using AAV [vectors].”
Indeed, Biogen started with zinc fingers, and is now adopting a lentivirus approach for the hemophilia therapies that was developed at TIGET; those viruses shepherd the functioning genes to the liver. The Italian institution has already been testing a hemophilia B treatment in experimental models, but will now expand to hemophilia A with Biogen’s support.
[Updated with Danos’ comments] Danos said if everything goes well, Biogen would like to begin the first clinical trial in 2016.
