New FIX versions may be used to create hemophilia B treatments
Such personalized replacement therapies may better control bleeding
Researchers have developed new versions of clotting factor IX (FIX) that may be used to create personalized treatments for people with hemophilia B — specifically, new replacement therapies designed to help more effectively control bleeding.
According to the team, the development of these new FIX versions may serve to create both short- and long-term therapies. The scientists noted that current hemophilia B treatments, while effective, must be given frequently to prevent and control bleeds.
“Several approaches have been explored to … enable less frequent dosing, and thus reduce the burden of treatment,” the researchers wrote, noting that this work has “implications for the development of tailorable [hemophilia B] replacement therapies.
The study describing the work, titled “Tailored collagen binding of albumin-fused hyperactive coagulation factor IX dictates in vivo distribution and functional properties,” was published in the journal Nature Communications.
A rare genetic bleeding disorder, hemophilia B is caused by mutations that lead to the reduced activity of the clotting protein FIX. Without functional FIX, blood cannot clot properly, putting hemophilia B patients at risk of experiencing prolonged bleeding episodes, and bleeding too easily.
Factor replacement therapy is standard treatment for hemophilia B
Standard treatment for hemophilia B involves factor replacement therapy, in which a working version of the missing or faulty FIX protein is administered into the body to restore blood clotting and help in the prevention or control of bleeding episodes. Although this type of treatment can be effective, a notable drawback is that the FIX protein itself is not very stable in the blood. As such, infusions need to be given frequently to maintain FIX activity high enough to prevent and control bleeds.
“There remains a substantial opportunity to enhance the design of FIX products,” Jan Terje Andersen, PhD, the study’s corresponding author at the University of Oslo in Norway, said in a press release detailing its findings. Andersen noted that better-designed products are needed “particularly to improve adherence to prophylactic [preventive] regimens that currently require frequent infusions.”
Together with colleagues from the University of Ferrara in Italy, Andersen’s team created new versions of FIX designed to be longer lasting than the naturally occurring protein.
To do this, the scientists first fused the FIX protein to another blood protein called albumin, which is typically very stable in the bloodstream. To maximize stability, the team specifically used a variant of the albumin protein that had been engineered to strongly bind to the neonatal Fc receptor — a protein that normally works to prevent the degradation and promote the recycling of antibodies and albumin circulating in the blood.
Scientist made changes to FIX protein to improve clotting ability
The team also made modifications to the FIX protein itself. One of these modifications was the introduction of the so-called Padua variant, which increases the protein’s activity and ability to form clots.
The FIX protein is normally active in the bloodstream, and when scientists measure its activity, they usually focus on the protein in the blood. But FIX can also exit the bloodstream and enter body tissues, which is important for normal clotting. FIX leaves the bloodstream by interacting with a structural protein called collagen IV.
The researchers also introduced two different modifications that either reduced (K5A) or enhanced (K5R) FIX’s ability to interact with collagen IV.
Through experiments in mouse models, the team found that the version of FIX that had been modified to strongly bind to collagen IV lasted about three times longer in the body, reaching a half-life of 80 hours. Half-life is the time it takes for the levels of a therapy or compound to drop to half of those originally given; the longer the half-life, the longer a compound remains active in the body.
This specific version of the protein was also better at getting outside blood vessels and into body tissues, the researchers noted.
Conversely, the version of FIX that had a reduced ability to bind to collagen IV had a negligible distribution outside blood vessels, while also reaching the highest levels in plasma — the non-cellular part of blood — shortly after being administered.
We firmly believe that such biology-guided protein designs can pave the way for more personalized treatment options [in hemophilia B].
“We demonstrate that [FIX bound to albumin] can be engineered for enhanced extravascular presence by introducing K5R to FIX, resulting in an attractive therapeutic candidate with improved biodistribution and favorable functional profile,” the team wrote. “Additionally, K5A engineering may provide a tool to improve on-demand treatment with an immediate need of increasing FIX levels in plasma.”
According to the scientists, these “findings support the use of [these variants] as hyperactive short- or long-term therapeutics, with implications for the development of tailorable [hemophilia B] replacement therapies,” they wrote, noting that additional work will be needed to move this into human testing.
Terje noted that the new FIX versions could lead to better replacement therapies for patients.
“We firmly believe that such biology-guided protein designs can pave the way for more personalized treatment options” in hemophilia B, Terje said.
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