title: Angiogenesis enhances factor IX delivery and persistence from retrievable human bioengineered muscle implants.
abstract: 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.
authors.affiliation: Center for Transgene Technology and Gene Therapy, University of Leuven/Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium.
authors.forename: Lieven
authors.initials: L
authors.lastname: Thorrez
authors.forename: Herman
authors.initials: H
authors.lastname: Vandenburgh
authors.forename: Nico
authors.initials: N
authors.lastname: Callewaert
authors.forename: Nico
authors.initials: N
authors.lastname: Mertens
authors.forename: Janet
authors.initials: J
authors.lastname: Shansky
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Jef
authors.initials: J
authors.lastname: Arnout
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Marinee
authors.initials: M
authors.lastname: Chuah
authors.forename: Thierry
authors.initials: T
authors.lastname: Vandendriessche
mesh_terms: 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
chemical_list: D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D005164:Factor IX