Paloma H. Giangrande

Cell-targeted RNA therapies for Hyperproliferative Cardiovascular Disease

William H Thiel1, Carla L Esposito2, David D Dickey1, Justin P Dassie1, Matthew E Long3, Joshua Adam1, Jennifer Streeter1, Brandon Schickling1, Maysam Takapoo1, Katie S Flenker1, Julia Klesney-Tait1, Vittorio de Franciscis2, Francis J Miller Jr1,4, Paloma H Giangrande1

1 Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
2 Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, Naples, Italy
3 Department of Microbiology, University of Washington, Seattle, WA 98109, USA
4 The Veterans Affair Medical Center, Iowa City, IA, USA 52242, USA

paloma-giangrande@uiowa.edu

Restenosis after stent deployment is an overreaction of the wound healing response after vascular injury characterized by a series of inflammatory events leading to pathologic smooth muscle cell activation. Recent advances in drug eluting stents (DES) have substantially reduced
restenosis. Nevertheless, DES do not contribute to improved long-term prognosis, compared to bare metal stents due to the non-specific effects of the antimitotic drugs (sirolimus and paclitaxel) on endothelial cells leading to impaired re-endothelialization, late stent thrombosis and death. To improve long-term prognosis in the DES era, cell-targeted therapies that selectively inhibit smooth muscle cell activation while enabling endothelial cell remodeling are needed. To address this need, we developed a synthetic RNA bio-drug that selectively targets smooth muscle cells but not endothelial cells or other types of myocytes. The RNA bio-drug inhibits protein kinase B (PKB)/Akt activation and smooth muscle cell migration in response to multiple agonists by a mechanism that involves inhibition of platelet-derived growth factor receptor (PDGFR)-beta-phosphorylation. In murine models of carotid injury, treatment of vessels with the RNA bio-drug reduces intimal hyperplasia to levels comparable to that of paclitaxel without hindering endothelial cell remodeling. Importantly, for downstream clinical applications, we verified that the RNA biodrug cross-reacts with both rodent and human smooth muscle cells, exhibits a long half-life (~300 hours) in human serum and is not pro-inflammatory or immunogenic. In conclusion, we will present the pre-clinical development of a novel, smooth muscle cell-targeted RNA bio-drug for the treatment of neointimal hyperplasia. In addition to the anticipated therapeutic benefit of celltargeted therapies for treating vascular disease, our work provides the essential foundation for the translation of synthetic RNA bio-drugs to multiple hyperplastic vascular diseases.