Effect of intramuscular baculovirus encoding mutant hypoxia-inducible factor 1-alpha on neovasculogenesis and ischemic muscle protection in rabbits with peripheral arterial disease |
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| Institution: | 1. Laboratorio de Medicina Regenerativa Cardiovascular, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Favaloro, Buenos Aires, Argentina;2. Laboratorio de Ingeniería Genética y Biología Celular y Molecular (LIGBCM), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Quilmes, Bernal, Argentina;3. Hospital Universitario de la Fundación Favaloro, Buenos Aires, Argentina;4. Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina;1. Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, Massachusetts, USA;2. The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA;3. Lung Bioengineering and Regeneration, Department of Experimental Medical Sciences, Faculty of Medicine, Lund University, Lund, Sweden;4. Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden;5. Wallenberg Molecular Medicine Center, Faculty of Medicine, Lund University, Lund, Sweden;6. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts, USA;7. Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA;8. Hastings Center for Pulmonary Research and Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA;9. Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, California, USA;1. Liver Tissue Engineering and Cell Therapy Laboratory, CHU Sainte-Justine, Montreal, Canada;2. Pediatric Hepatology, CHU Sainte-Justine, Montreal, Canada;3. Department of Pediatrics, Université de Montréal, Montreal, Canada |
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| Abstract: | Background aimsPeripheral arterial disease (PAD) is a progressive, disabling ailment for which no effective treatment exists. Gene therapy-mediated neovascularization has emerged as a potentially useful strategy. We tested the angiogenic and arteriogenic efficacy and safety of a baculovirus (BV) encoding mutant, oxygen-resistant hypoxia-inducible factor 1-alpha (mHIF-1α), in rabbits with PAD.MethodsAfter assessing the transfection efficiency of the BV.mHIF-1α vector and its tubulogenesis potential in vitro, we randomized rabbits with experimental PAD to receive 1 × 109 copies of BV.mHIF-1α or BV.null (n = 6 per group) 7 days after surgery. Two weeks post-treatment, collateralization (digital angiography) and capillary and arteriolar densities (immunohistochemistry) were measured in the posterior limbs. Ischemic damage was evaluated in adductor and gastrocnemius muscle samples. Tracking of viral DNA in injected zones and remote tissues at different time points was performed in additional rabbits using a BV encoding GFP.ResultsAngiographically visible collaterals were more numerous in BV.mHIF-1α-treated rabbits (8.12 ± 0.42 vs 6.13 ± 1.15 collaterals/cm2, P < 0.05). The same occurred with arteriolar (27.9 ± 7.0 vs 15.3 ± 4.0 arterioles/mm2) and capillary (341.8 ± 109.9 vs 208.8 ± 87.7 capillaries/mm2, P < 0.05) densities. BV.mHIF-1α-treated rabbits displayed less ischemic muscle damage than BV.null-treated animals. Viral DNA and GFP mRNA were detectable only at 3 and 7 days after injection in hind limbs. Neither the virus nor GFP mRNA was detected in remote tissues.ConclusionsIn rabbits with PAD, BV.mHIF-1α induced neovascularization and reduced ischemic damage, exhibiting a good safety profile at 14 days post-treatment. Complementary studies to evaluate its potential usefulness in the clinic are needed. |
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