title: Long-term safety and stability of angiogenesis induced by balanced single-vector co-expression of PDGF-BB and VEGF164 in skeletal muscle.
abstract: Therapeutic angiogenesis by growth factor delivery is an attractive treatment strategy for ischemic diseases, yet clinical efficacy has been elusive. The angiogenic master regulator VEGF-A can induce aberrant angiogenesis if expressed above a threshold level. Since VEGF remains localized in the matrix around expressing cells, homogeneous dose distribution in target tissues is required, which is challenging. We found that co-expression of the pericyte-recruiting factor PDGF-BB at a fixed ratio with VEGF from a single bicistronic vector ensured normal angiogenesis despite heterogeneous high VEGF levels. Taking advantage of a highly controlled gene delivery platform, based on monoclonal populations of transduced myoblasts, in which every cell stably produces the same amount of each factor, here we rigorously investigated a) the dose-dependent effects, and b) the long-term safety and stability of VEGF and PDGF-BB co-expression in skeletal muscle. PDGF-BB co-expression did not affect the normal angiogenesis by low and medium VEGF doses, but specifically prevented vascular tumors by high VEGF, yielding instead normal and mature capillary networks, accompanied by robust arteriole formation. Induced angiogenesis persisted unchanged up to 4 months, while no tumors appeared. Therefore, PDGF-BB co-expression is an attractive strategy to improve safety and efficacy of therapeutic angiogenesis by VEGF gene delivery.
authors.affiliation: Cell and Gene Therapy, Department of Biomedicine, Basel University, Basel, Switzerland.|Department of Surgery, Basel University Hospital, Basel, Switzerland.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gianni-Barrera
authors.affiliation: Cell and Gene Therapy, Department of Biomedicine, Basel University, Basel, Switzerland.|Department of Surgery, Basel University Hospital, Basel, Switzerland.|Plastic, Reconstructive, Aesthetic and Hand Surgery, Basel University Hospital, Basel, Switzerland.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Burger
authors.affiliation: Cell and Gene Therapy, Department of Biomedicine, Basel University, Basel, Switzerland.|Department of Surgery, Basel University Hospital, Basel, Switzerland.|Vascular Surgery, Basel University Hospital, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolff
authors.affiliation: Cell and Gene Therapy, Department of Biomedicine, Basel University, Basel, Switzerland.|Department of Surgery, Basel University Hospital, Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Heberer
authors.affiliation: Plastic, Reconstructive, Aesthetic and Hand Surgery, Basel University Hospital, Basel, Switzerland.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Schaefer
authors.affiliation: Vascular Surgery, Basel University Hospital, Basel, Switzerland.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Gürke
authors.affiliation: Cell and Gene Therapy, Department of Biomedicine, Basel University, Basel, Switzerland.|Department of Surgery, Basel University Hospital, Basel, Switzerland.|Vascular Surgery, Basel University Hospital, Basel, Switzerland.
authors.forename: Edin
authors.initials: E
authors.lastname: Mujagic
authors.affiliation: Cell and Gene Therapy, Department of Biomedicine, Basel University, Basel, Switzerland.|Department of Surgery, Basel University Hospital, Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Banfi
mesh_terms: D000818:Animals; D000077214:Becaplermin; D015870:Gene Expression; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics*; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism / Q000637:transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin