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Transfer of BMPR2 Protein to Human Pulmonary Artery Endothelial Cells Using Designed Microvesicles
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A2069 - Transfer of BMPR2 Protein to Human Pulmonary Artery Endothelial Cells Using Designed Microvesicles
Author Block: J. Jang1, R. L. Benza2, M. Passineau3; 1Allegheny-Singer Research Institute, Pittsburgh, PA, United States, 2Allegheny General Hosp, Pittsburgh, PA, United States, 3Allegheny-Singer Research Inst, Pittsburgh, PA, United States.
Rationale Bone morphogenic receptor type 2 (BMPR2) is one of the genetic roots underlying most heritable forms of pulmonary arterial hypertension (PAH) and plays an central role in pathophysiology. The loss of BMPR2 activity in the pulmonary vascular endothelium conspires with a cabal of cellular and environment factors to effect endothelial dysfunction. Intriguingly, recent research interrogating explanted and cadaveric lungs from PAH patients has demonstrated that BMPR2 protein is reduced in the pulmonary endothelium of PAH patients who do not harbor the hereditable BMPR2 mutation. We envision a disease-modifying therapy capable delivering therapeutic proteins (e.g. BMPR2) directly into the cells of the pulmonary endothelium using extracellular vesicles (EVs). Methods Our group, working at Allegheny Health Network and Northwestern University has been developing extracellular vesicles (e.g. exosomes and microvesicles) as novel candidate biopharmaceutical agents for delivering functional transmembrane proteins to the surface of human pulmonary artery endothelial cells (hPAECs). In the course of this ongoing work, we have made the novel observation that microvesicles (MVs) can deliver a functional transmembrane protein analogous to BMPR2 to the surface of hPAECs, whereas isogenic exosomes (Exos) carrying the same protein cannot. Results We have developed a novel BMPR2-loaded MV and using this MV have succeeded in delivering BMPR2 to the surface of hPAECs in vitro. Conclusions We conclude that BMPR2-MVs are a novel biopharmaceutical agent capable of augmenting or replacing BMPR2 protein in hPAECs. These studies create a rationale for transitioning of this promising therapeutic technology to animal studies.
Author Block: J. Jang1, R. L. Benza2, M. Passineau3; 1Allegheny-Singer Research Institute, Pittsburgh, PA, United States, 2Allegheny General Hosp, Pittsburgh, PA, United States, 3Allegheny-Singer Research Inst, Pittsburgh, PA, United States.
Rationale Bone morphogenic receptor type 2 (BMPR2) is one of the genetic roots underlying most heritable forms of pulmonary arterial hypertension (PAH) and plays an central role in pathophysiology. The loss of BMPR2 activity in the pulmonary vascular endothelium conspires with a cabal of cellular and environment factors to effect endothelial dysfunction. Intriguingly, recent research interrogating explanted and cadaveric lungs from PAH patients has demonstrated that BMPR2 protein is reduced in the pulmonary endothelium of PAH patients who do not harbor the hereditable BMPR2 mutation. We envision a disease-modifying therapy capable delivering therapeutic proteins (e.g. BMPR2) directly into the cells of the pulmonary endothelium using extracellular vesicles (EVs). Methods Our group, working at Allegheny Health Network and Northwestern University has been developing extracellular vesicles (e.g. exosomes and microvesicles) as novel candidate biopharmaceutical agents for delivering functional transmembrane proteins to the surface of human pulmonary artery endothelial cells (hPAECs). In the course of this ongoing work, we have made the novel observation that microvesicles (MVs) can deliver a functional transmembrane protein analogous to BMPR2 to the surface of hPAECs, whereas isogenic exosomes (Exos) carrying the same protein cannot. Results We have developed a novel BMPR2-loaded MV and using this MV have succeeded in delivering BMPR2 to the surface of hPAECs in vitro. Conclusions We conclude that BMPR2-MVs are a novel biopharmaceutical agent capable of augmenting or replacing BMPR2 protein in hPAECs. These studies create a rationale for transitioning of this promising therapeutic technology to animal studies.
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