TY - JOUR
T1 - GP64-pseudotyped lentiviral vectors target liver endothelial cells and correct hemophilia A mice
AU - Milani, Michela
AU - Canepari, Cesare
AU - Assanelli, Simone
AU - Merlin, Simone
AU - Borroni, Ester
AU - Starinieri, Francesco
AU - Biffi, Mauro
AU - Russo, Fabio
AU - Fabiano, Anna
AU - Zambroni, Desirèe
AU - Annoni, Andrea
AU - Naldini, Luigi
AU - Follenzi, Antonia
AU - Cantore, Alessio
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/6/14
Y1 - 2024/6/14
N2 - Lentiviral vectors (LV) are efficient vehicles for in vivo gene delivery to the liver. LV integration into the chromatin of target cells ensures their transmission upon proliferation, thus allowing potentially life-long gene therapy following a single administration, even to young individuals. The glycoprotein of the vesicular stomatitis virus (VSV.G) is widely used to pseudotype LV, as it confers broad tropism and high stability. The baculovirus-derived GP64 envelope protein has been proposed as an alternative for in vivo liver-directed gene therapy. Here, we perform a detailed comparison of VSV.G- and GP64-pseudotyped LV in vitro and in vivo. We report that VSV.G-LV transduced hepatocytes better than GP64-LV, however the latter showed improved transduction of liver sinusoidal endothelial cells (LSEC). Combining GP64-pseudotyping with the high surface content of the phagocytosis inhibitor CD47 further enhanced LSEC transduction. Coagulation factor VIII (FVIII), the gene mutated in hemophilia A, is naturally expressed by LSEC, thus we exploited GP64-LV to deliver a FVIII transgene under the control of the endogenous FVIII promoter and achieved therapeutic amounts of FVIII and correction of hemophilia A mice.
AB - Lentiviral vectors (LV) are efficient vehicles for in vivo gene delivery to the liver. LV integration into the chromatin of target cells ensures their transmission upon proliferation, thus allowing potentially life-long gene therapy following a single administration, even to young individuals. The glycoprotein of the vesicular stomatitis virus (VSV.G) is widely used to pseudotype LV, as it confers broad tropism and high stability. The baculovirus-derived GP64 envelope protein has been proposed as an alternative for in vivo liver-directed gene therapy. Here, we perform a detailed comparison of VSV.G- and GP64-pseudotyped LV in vitro and in vivo. We report that VSV.G-LV transduced hepatocytes better than GP64-LV, however the latter showed improved transduction of liver sinusoidal endothelial cells (LSEC). Combining GP64-pseudotyping with the high surface content of the phagocytosis inhibitor CD47 further enhanced LSEC transduction. Coagulation factor VIII (FVIII), the gene mutated in hemophilia A, is naturally expressed by LSEC, thus we exploited GP64-LV to deliver a FVIII transgene under the control of the endogenous FVIII promoter and achieved therapeutic amounts of FVIII and correction of hemophilia A mice.
KW - Envelope Engineering
KW - Hemophilia A
KW - In Vivo Gene Therapy
KW - Lentiviral Vectors
KW - Liver Endothelial Cells
UR - http://www.scopus.com/inward/record.url?scp=85191848963&partnerID=8YFLogxK
U2 - 10.1038/s44321-024-00072-8
DO - 10.1038/s44321-024-00072-8
M3 - Article
SN - 1757-4676
VL - 16
SP - 1427
EP - 1450
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 6
ER -