Effect of intramuscular baculovirus encoding mutant hypoxia-inducible factor 1-alpha on neovasculogenesis and ischemic muscle protection in rabbits with peripheral arterial disease

GIMÉNEZ, CARLOS SEBASTIÁN; NUÑEZ PEDROZO, CRISTIAN; LOCATELLI, PAOLA; MÉNDIZ, OSCAR; OLEA, FERNANDA DANIELA; CASTILLO, MARTHA GIOVANNA; PASCUALI, NATALIA; LÓPEZ, AYELÉN EMILCE; CROTTOGINI, ALBERTO; SIMONIN, ALEJANDRO; BAUZÁ, MARIA DEL ROSARIO; BELAICH, MARIANO NICOLÁS; CUNIBERTI, LUIS

CYTOTHERAPY

TAYLOR & FRANCIS AS

Lugar: Londres; Año: 2020 vol. 22 p. 563 - 572

1465-3249

Background aims: Peripheral arterial disease (PAD) is a progressive, disabling ailment for which no effectivetreatment 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-1a), in rabbits with PAD.Methods: After assessing the transfection efficiency of the BV.mHIF-1a vector and its tubulogenesis potential invitro, we randomized rabbits with experimental PAD to receive 1 £ 109 copies of BV.mHIF-1a or BV.null (n = 6per group) 7 days after surgery. Two weeks post-treatment, collateralization (digital angiography) and capillaryand arteriolar densities (immunohistochemistry) were measured in the posterior limbs. Ischemic damage wasevaluated in adductor and gastrocnemius muscle samples. Tracking of viral DNA in injected zones and remotetissues at different time points was performed in additional rabbits using a BV encoding GFP.Results: Angiographically visible collaterals were more numerous in BV.mHIF-1a-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 § 4.0arterioles/mm2) and capillary (341.8 § 109.9 vs 208.8 § 87.7 capillaries/mm2, P < 0.05) densities. BV.mHIF1a-treated rabbits displayed less ischemic muscle damage than BV.null-treated animals. Viral DNA and GFPmRNA were detectable only at 3 and 7 days after injection in hind limbs. Neither the virus nor GFP mRNAwas detected in remote tissues.Conclusions: In rabbits with PAD, BV.mHIF-1a induced neovascularization and reduced ischemic damage,exhibiting a good safety profile at 14 days post-treatment. Complementary studies to evaluate its potentialusefulness in the clinic are needed.