Sustained high expression of human FVII following AAV8-mediated gene delivery in mice

TY - JOUR

T1 - Sustained high expression of human FVII following AAV8-mediated gene delivery in mice

AU - D'Amico, Andrea

AU - Blits, Bas

AU - van den Herik, Joëlle

AU - de Winter, Fred

AU - Kaijen, Paul H P

AU - Hobo, Barbara

AU - van Asbeck, Alexander Henrik

AU - Verhaagen, Joost

AU - Mosmuller, David G M

AU - Voorberg, Jan

N1 - © 2025 The Authors.

PY - 2025/9/11

Y1 - 2025/9/11

N2 - Factor VII (FVII) deficiency is a rare bleeding disorder with a prevalence of approximately 1:300,000-500,000 individuals. We explored whether adeno-associated virus (AAV)-mediated gene therapy can achieve durable and functional expression of human FVII (hFVII) in vivo. Wild-type hFVII (hFVIIwt) and a naturally occurring splice variant designated hFVII(-22) (GenBank: NM_019616.4) were expressed under the control of the Apolipoprotein E-derived hepatic locus control region and the α1-anti-trypsin promoter. Expression cassettes were packaged in either recombinant AAV5 (rAAV5) or recombinant AAV8 (rAAV8). For both hFVIIwt and hFVII(-22), 5- to 20-fold higher plasma levels of hFVII could be obtained when rAAV8 was used as a vector as opposed to rAAV5. Interestingly, hFVII levels obtained by employing rAAV8 expressing the hFVII(-22) cDNA variant were approximately 10 times higher than those obtained using rAAV8 expressing hFVIIwt. Based on these results, we generated an rAAV8-based gene therapy vector encoding hFVII(-22) and evaluated long-term expression in vivo. Employing a vector dose of 0.8 × 1012 genome copies (gc)/kg, we observed 48 weeks of functional hFVII expression which peaked at 16 IU/mL and stabilized at 7 IU/mL. These results support the pre-clinical development of AAV8-mediated delivery employing the splice-variant hFVII(-22) for patients suffering from FVII deficiency.

AB - Factor VII (FVII) deficiency is a rare bleeding disorder with a prevalence of approximately 1:300,000-500,000 individuals. We explored whether adeno-associated virus (AAV)-mediated gene therapy can achieve durable and functional expression of human FVII (hFVII) in vivo. Wild-type hFVII (hFVIIwt) and a naturally occurring splice variant designated hFVII(-22) (GenBank: NM_019616.4) were expressed under the control of the Apolipoprotein E-derived hepatic locus control region and the α1-anti-trypsin promoter. Expression cassettes were packaged in either recombinant AAV5 (rAAV5) or recombinant AAV8 (rAAV8). For both hFVIIwt and hFVII(-22), 5- to 20-fold higher plasma levels of hFVII could be obtained when rAAV8 was used as a vector as opposed to rAAV5. Interestingly, hFVII levels obtained by employing rAAV8 expressing the hFVII(-22) cDNA variant were approximately 10 times higher than those obtained using rAAV8 expressing hFVIIwt. Based on these results, we generated an rAAV8-based gene therapy vector encoding hFVII(-22) and evaluated long-term expression in vivo. Employing a vector dose of 0.8 × 1012 genome copies (gc)/kg, we observed 48 weeks of functional hFVII expression which peaked at 16 IU/mL and stabilized at 7 IU/mL. These results support the pre-clinical development of AAV8-mediated delivery employing the splice-variant hFVII(-22) for patients suffering from FVII deficiency.

U2 - 10.1016/j.omtm.2025.101523

DO - 10.1016/j.omtm.2025.101523

M3 - Article

C2 - 40697775

SN - 2329-0501

VL - 33

SP - 101523

JO - Molecular therapy. Methods & clinical development

JF - Molecular therapy. Methods & clinical development

IS - 3

ER -