Coagulation Factor IX (modified FIX-FIAV) (FIX-FIAV)

Coagulation Factor IX (modified FIX-FIAV) is an engineered variant of the human serine protease Factor IX (FIX), specifically designed to function independently of its natural cofactor, Factor VIIIa (FVIIIa) [1.1.2, 1.3.1]. This variant incorporates four specific amino acid substitutions—L6F, V181I, K265A, and I383V—which modify the 99-loop and the S1 active-site subpocket of the enzyme to enhance its catalytic efficiency toward Factor X (FX) [1.1.2, 1.3.1]. These modifications allow the activated form of the protein (FIXa-FIAV) to activate FX at a rate sufficient to support blood clotting even in the absence of Factor VIII, effectively serving as a "bypass" therapy for Hemophilia A [1.1.2, 1.3.2]. The primary therapeutic potential of FIX-FIAV lies in treating Hemophilia A patients, particularly those with inhibitory antibodies against Factor VIII that complicate standard replacement therapies [1.3.1, 1.3.2]. By providing a Factor VIII-independent pathway for thrombin generation, FIX-FIAV can restore hemostasis and reduce bleeding episodes [1.3.2, 1.3.3]. It has been primarily investigated as a gene therapy candidate, such as uniQure's AMT-180, which utilizes an adeno-associated virus (AAV) vector for long-term endogenous expression [1.2.1, 1.2.2]. Clinical development has focused on its ability to improve clotting activity while monitoring for safety concerns such as unintended thrombosis and immunogenicity [1.2.1, 1.2.4]. Although the development of AMT-180 was suspended by its developer, the FIX-FIAV molecule remains a significant proof-of-concept for cofactor-independent coagulation factors [1.1.3, 1.2.4].

Other names

AMT-180FVIII-independent Factor IXCofactor-independent Factor IXFIX-FIAV variantFIX-FIAV

FIX-FIAV activates Factor X (FX) independently of the cofactor Factor VIIIa (FVIIIa), thereby bypassing the need for Factor VIII in the coagulation cascade [1.1.2, 1.3.1].