Intramyocardial baculovirus-Meis1 gene therapy induces angio-arteriogenesis in sheep with myocardial infarction.

Abstract

BACKGROUND: Ischemic heart disease is the cardiovascular condition with the highest morbidity and mortality worldwide, highlighting the need for therapies aimed at promoting neovascularization of the ischemic myocardium. Given the involvement of the transcription factor Myeloid ecotropic viral integration site 1 (MEIS1) in the development of the vascular network in vertebrates, we hypothesized that MEIS1 overexpression would induce microvascular proliferation in an ovine model of acute myocardial infarction. METHODS: A baculoviral vector encoding MEIS1 (Bv.Meis1) was designed and injected into the peri-infarct zone of adult sheep with permanent coronary ligation. Control sheep were injected with an empty baculovirus (Bv.Null). One week later, microvascular densities and expression of angiogenic genes were assessed in myocardial tissue samples. RESULTS: Animals treated with Bv.Meis1 exhibited significantly greater capillary and arteriolar densities as well as a significant increase in the expression of Vegf, Angiogenin, Hif1α, Igf, Fgf2 and Prok2, compared to Bv.Null group. Additionally, overexpression of most of these genes was also found in cultures of neonatal rat cardiomyocytes transduced with Bv.Meis1, and increased tubulogenesis was observed in HMEC-1 cells incubated with supernatants of these cultures. Finally, the vector's biosafety was demonstrated by the absence of viral DNA expression in tissues remote to the heart. CONCLUSIONS: Intramyocardial injection of a baculovirus encoding MEIS1 promotes overexpression of angiogenic genes which, in turn, induce angio-arteriogenesis in ovine myocardial infarction. Given the highly translational nature of the animal model and the good biosafety profile of the baculoviral vector, this strategy could potentially be useful for patients with ischemic heart disease.