Enhanced Hemophilia B Treatment: Engineered Albumin-Fused FIX Extends Half-Life

Researchers have developed a groundbreaking approach to improve hemophilia B treatment by engineering novel albumin-fused coagulation factor IX (FIX) proteins. Hemophilia B, caused by a deficiency in FIX, results in impaired blood clotting and prolonged bleeding episodes following injuries or surgeries. Traditional replacement therapy with recombinant FIX offers significant benefits but requires frequent injections due to its limited plasma half-life of approximately 3–4 days.

To address this issue, scientists from the University of Oslo and the University of Ferrara have designed long-lasting FIX variants by fusing them with a specially engineered human albumin. This albumin variant, featuring three amino acid substitutions (E505Q/T527M/K573P, known as QMP), has enhanced binding affinity for the neonatal Fc receptor (FcRn), a key protein involved in prolonging protein circulation in the bloodstream.

The fused FIX proteins incorporate the hyperactive R338L (Padua) mutation, which boosts activity, along with modifications affecting interaction with collagen IV in tissues—specifically, replacing lysine (K5) with either alanine (K5A) to reduce affinity or arginine (K5R) to increase it. These alterations influence the distribution and retention of FIX in tissues, with K5R enhancing extravascular localization and thereby extending the functional half-life of the therapy up to three times longer in animal models.

Importantly, the engineered FIX proteins can be cleaved from albumin upon activation, ensuring their proper functional role in blood clotting. Mouse studies demonstrated that the K5R variant significantly improved both distribution and longevity, suggesting potential for personalized therapeutic strategies. The research indicates that albumin-fused FIX variants—particularly Padua K5A and K5R—could serve as short- or long-term options, reducing the frequency of injections required for patients.

Historically, severe hemophilia B impacted life expectancy due to bleeding complications. Advances in biotechnology, including these engineered proteins, aim to enhance treatment efficacy and patient adherence. This innovation underscores the potential to tailor therapies based on individual needs, ultimately improving quality of life for those with hemophilia B.

According to Professor Jan Terje Andersen, the use of biology-guided protein design, such as these albumin-fused FIXs, could revolutionize personalized hemophilia treatment, making therapies more effective and convenient. The research was published in Nature Communications and highlights the promising future of enzymatic engineering in bleeding disorder management.