GENV-HEM
Liver-directed expression of activated Factor V: an investigational approach to hemophilia A, with or without FVIII inhibitors.
Explore the science ↓Understanding normal blood clotting
Normal blood clotting depends on a coordinated sequence of reactions involving specialized proteins known as coagulation factors. When a blood vessel is injured, these factors work together to generate thrombin, which converts fibrinogen into fibrin. The resulting fibrin network helps stabilize the developing blood clot and control bleeding.
Factor VIII (FVIII) and factor IX (FIX) are essential components of this process. Activated FVIII acts as a cofactor for activated FIX, enabling efficient activation of factor X (FX). This contributes to thrombin generation and, ultimately, the formation of a stable fibrin clot.
When the clotting process is disrupted
Hemophilia is an inherited bleeding disorder characterized by a deficiency or dysfunction of specific coagulation factors. Hemophilia A results from insufficient functional FVIII, while hemophilia B results from insufficient functional FIX.
When either factor is deficient, efficient FX activation is impaired, reducing thrombin generation and the formation of a stable fibrin clot. This can lead to prolonged bleeding, spontaneous bleeding episodes, and recurrent bleeding into joints and muscles. Over time, repeated bleeding may cause progressive joint damage and affect quality of life.
GENV-HEM: Liver-directed expression of activated Factor V
GENV-HEM is an investigational gene therapy approach for hemophilia A, with or without FVIII inhibitors.
Rather than replacing deficient FVIII directly, GENV-HEM is designed to deliver a gene encoding activated human Factor V (FVa), a cofactor that supports thrombin generation downstream of the FVIII- and FIX-dependent step.
The approach uses an adeno-associated virus serotype 8 (AAV8) vector and a liver-specific promoter to direct FVa expression in hepatocytes. The therapeutic concept is that liver-produced FVa enters the circulation and may support thrombin generation and clot formation only at the site of injury.
Supporting thrombin generation downstream of FVIII and FIX
GENV-HEM is designed to provide circulating activated Factor V (FVa). Rather than replacing either deficient factor, FVa is intended to support FXa activity downstream of the FVIII/FIX-dependent step, including in the presence of FVIII inhibitors.
At the site of injury, FVa and FXa can assemble into the prothrombinase complex on appropriate phospholipid surfaces. This complex converts prothrombin into thrombin, which converts fibrinogen into fibrin and helps form a stable clot.
By providing FVa through liver-directed gene expression, GENV-HEM aims to support hemostasis in hemophilia A, with or without FVIII inhibitors.
A mechanism designed with coagulation regulation in mind
GENV-HEM is designed to provide activated Factor V (FVa), a naturally occurring cofactor that supports thrombin generation downstream of the FVIII-dependent step.
FVa is subject to physiological anticoagulant regulation, including inactivation by activated protein C (APC). This endogenous mechanism helps regulate FVa activity and thrombin generation.
By expressing FVa that retains susceptibility to physiological anticoagulant regulation, GENV-HEM aims to support hemostasis while preserving an important mechanism of coagulation control.
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