Rendering factor Xa zymogen-like as a therapeutic strategy to treat bleeding

Abstract

Purpose of review New therapies are needed to control bleeding in a range of clinical conditions. This review will discuss the biochemical properties of zymogen-like FXa, its pre-clinical assessment in different model systems, and future development prospects. Recent findings Underlying many procoagulant therapeutic approaches is the rapid generation of thrombin to promote robust clot formation. Clinically tested prohemostatic agents (e.g factor VIIa) can provide effective hemostasis to mitigate bleeding in hemophilia and other clinical situations. Over the past decade, we explored the possibility of using zymogen-like FXa variants to rapidly improve clot formation for the treatment of bleeding conditions. Compared to the wild-type enzyme, these variants adopt an altered, low activity, conformation which enables them to resist plasma protease inhibitors. However, zymogen-like FXa variants are conformationally dynamic and ligands such as its cofactor, FVa, stabilize the molecule rescuing procoagulant activity. At the site of vascular injury, the variants in the presence of FVa serve as effective prohemostatic agents. Pre-clinical data support their use to stop bleeding in a variety of clinical settings. Phase 1 studies suggest that zymogen-like FXa is safe and well-tolerated, and a phase 1b is ongoing to assess safety in patients with intracerebral hemorrhage. Summary Zymogen-like FXa is a unique prohemostatic agent for the treatment of a range of bleeding conditions.

Activated Factor X delivered by Adeno-Associated virus significantly inhibited bleeding and alleviated hemophilia A/B arthropathy in hemophilia mice

“…Recently, several long-acting FXa that was developed by changing the amino acid composition structure were used to clinical trial. The results showed that patients were highly tolerated and safe, and suppressed acute intracranial hemorrhage of patients [12,13] . These studies suggested that the treatment of hemophilia can also be achieved by intervening in the components of the "bypass" coagulation pathway.…”

Directed Evolution Methods for Enzyme Engineering

“…Enzymes catalyze all the fundamental transformations required to convert matter and energy into living systems. Society has benefited profusely from adaptation of pre-existing enzymes for industrial, research and medical uses [ 1 , 2 , 3 , 4 , 5 , 6 ]. However, pre-existing enzymes are often not optimal for industrial applications due to temperature, pH and solvent stability, as well as substrate specificity and activity limitations [ 7 , 8 , 9 , 10 ].…”