Novel factor VIIa chimeras for safer hemostasis
Chronic wounds impact 6.5 million patients in the US, leading to complications such as infections, hemorrhage, gangrene, and amputations. The resulting health burden costs the US healthcare system an estimated $25 billion annually and is only expected to rise in the future. Currently, topically applied activated protein C (APC) is a primary treatment available for chronic wounds. While use of Factor VIIa is a common treatment for hemophilia-related surgical or trauma-related bleeding, it could potentially be another treatment chronic wounds, though it remains currently untested clinically.
Both APC and FVIIa improve chronic wounds through mechanisms that induce anti-inflammatory signaling pathways, inhibit pro-inflammatory factors, and maintain vascular barrier integrity. However, in their current forms, both treatments have significant limitations. APC can interfere with hemostasis required for wound closing, increasing long-term inflammation. FVIIa, on the other hand, can induce a burst of pro-inflammatory factors and reduce the integrity of the vascular barrier during the process of hemostasis. As such, there is a need for therapeutic agents that not only stabilize the vascular barrier but also improve hemostasis in a targeted and effective manner.
Duke inventors have developed novel chimeric variants of FVIIa to treat chronic wounds and associated prolonged inflammation. These are intended to be used as an effective dose of chimeric FVIIa delivered by a clinician as either a topical treatment, an intravenous or subcutaneous injection, or a therapeutic formulation. The therapy can be intended as a treatment for wounds, inflammation, or hemorrhagic conditions as well as for preventing cell-death. Specifically, Duke inventors have created Protein C-FVII (PC-FVII) and activated form (PC-FVIIa) by combining structural domains from APC and FVIIa encoding desired functionality while excluding domains with undesired activity. This has been demonstrated through both in-vitro and in-vivo experiments evaluating the reduced interaction of PC- FVIIa with pro-inflammatory factors and increased efficacy in inducing anti-inflammatory and hemostatic activity as well as barrier stabilization.
This technology could also be used to treat acute bleeding such as that resulting from traumatic brain injury, intracerebral hemorrhage, and hemorrhagic stroke.
- Effective hemostasis without interaction with pro-inflammatory factors.
- Improved anti-inflammatory effects, bleeding control, and vascular barrier stabilization compared to current treatments.
- Reduced risk of thrombosis-related complications.
- Reduced apoptosis-related cell death.