Ex vivo lentiviral gene therapy for severe hemophilia A: an alternative to recombinant adeno-associated viral-based strategies?

Authors: Samelson-Jones, BJ

Affiliations: Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA; Univ Penn, Perelman Sch Med, Dept Pediat, Div Hematol, Philadelphia, PA.

Publication:USA Research and Practice in Thrombosis and Haemostasis ; 2025 ; 9

ABSTRACT: The definitive goal of hemophilia A (HA) gene therapy is to safely impart sustained factor (F)VIII activity that normalizes hemostasis and optimizes well-being for all people with hemophilia [1–5]. Three decades of translational studies have mostly focused on recombinant adeno-associated viral (rAAV) vector-based strategies to target hepatocytes in vivo [3–5], though cell-based gene strategies were one of the earliest approaches clinically evaluated [6]. Advances in rAAV-based gene therapy have resulted in the recent approval of valoctocogene roxaparvovec for severe HA, as well as rAAV-

based drugs for hemophilia B and other monogenic disorders. Though a landmark in hemophilia therapeutics, the current generation of rAAV-based drugs for HA has several limitations: 1) they are restricted to adult males without preexisting anti-AAV antibodies; 2) there is substantial variability in FVIII levels, which range from supratherapeutic to unmeasurably low; 3) high FVIII levels are unstable with a marked decrease from year 1 to year 6; and 4) a multimillion-dollar price [3–5,7]. Innovations are needed to overcome these limitations and fulfill the promise of gene therapy.