Angiogenesis enhances factor IX delivery and persistence from retrievable human bioengineered muscle implants.
Human muscle progenitor cells transduced with lentiviral vectors secreted high levels of blood clotting factor IX (FIX). When bioengineered into postmitotic myofibers as human bioartificial muscles (HBAMs) and subcutaneously implanted into immunodeficient mice, they secreted FIX into the circulation for >3 months. The HBAM-derived FIX was biologically active, consistent with the cells' ability to conduct the necessary posttranslational modifications. These bioengineered muscle implants are retrievable, an inherent safety feature that distinguishes this "reversible" gene therapy approach from most other gene therapy strategies. When myofibers were bioengineered from human myoblasts expressing FIX and vascular endothelial growth factor, circulating FIX levels were increased and maintained long term within the therapeutic range, consistent with the generation of a vascular network around the HBAM. The present study implicates an important role for angiogenesis in the efficient delivery of therapeutic proteins using tissue engineered stem cell-based gene therapies.
Thorrez
Lieven
L
Center for Transgene Technology and Gene Therapy, University of Leuven/Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium.
Vandenburgh
Herman
H
Callewaert
Nico
N
Mertens
Nico
N
Shansky
Janet
J
Wang
Lin
L
Arnout
Jef
J
Collen
Désiré
D
Chuah
Marinee
M
Vandendriessche
Thierry
T
D000818:Animals; D005164:Factor IX / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D006467:Hemophilia A / Q000628:therapy*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D032448:Myoblasts, Skeletal / Q000378:metabolism* / Q000637:transplantation*; D018919:Neovascularization, Physiologic / Q000235:genetics; D023822:Tissue Engineering; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D005164:Factor IX