Dysfunctional endothelium contributes to more disease than any other tissue in the body. Two types of small ribonucleic acid (RNA) molecules – microRNA (miRNA) and small interfering RNA(siRNA) – are central to RNA interference (RNAi). These RNAi molecules have the potential to help study and treat endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient RNA delivery has so far remained challenging.Our polymeric nanoparticle named 7C1, were discovered at M.I.T. and are made of low molecular weight polyamines and lipids that can deliver these RNAs to endothelial cells with high efficiency, thereby facilitating the simultaneous modification of expression of multiple endothelial genes in vivo. Unlike most nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene expression modulation. It mediates the most durable non-liver silencing reported to date, and facilitates the delivery of RNAs that modify endothelial function in mouse models of atherosclerosis, pulmonary hypertension, vascular permeability, emphysema, primary tumor growth, and metastasis. We believe our nanoparticles improve the ability to study endothelial gene function in vivo, and may be used to treat diseases caused by vascular dysfunction.
TGFβ, a member of the TGF superfamily of growth factors, has been reported to be involved in a wide range of diverse and often contradictory functions. Therefore, selective delivery targeting this pathway is critical for development of safe and effective therapeutics. VasoRx utilizes novel nanoparticles developed at M.I.T. that preferentially target the endothelium versus the underlying tissue.
Figure 1: Selective delivery of fluorescent tagged RNAi to endothelial cells using our proprietary 7C1 nanoparticle formulation. Immunofluorescent examination of the mouse aorta after intravenous in vivo delivery demonstrated the presence of a reporter tagged Alexa647 RNAi signal only in luminal endothelial cells (green) and not the underlying tissue, including vascular smooth muscle cells. Nuclei were counterstained with DAPI (blue).
VasoRx is evaluating a variety of indications including:
- Atherosclerosis: Our lead program is targeting atherosclerosis, which is a progressive vascular disease triggered by interplay between abnormal shear stress and endothelial lipid retention. A combination of these and, potentially, other factors leads to a chronic inflammatory response in the vessel wall, which is thought to be responsible for disease progression characterized by a buildup of atherosclerotic plaques. Our Founders at Yale have shown that endothelial TGF-β signaling is one of the primary drivers of atherosclerosis-associated vascular inflammation. Endothelial TGFβ signaling as an important driver of atherosclerotic plaque growth via induction of endothelial to mesenchymal transition (EndMT). Inhibition of endothelial TGFβ signaling in hyperlipidemic mice reduces vessel wall inflammation and vascular permeability and leads to arrest of disease progression and regression of established lesions. These pro-inflammatory effects of endothelial TGFβ signaling are in stark contrast with its effects in other cell types and identify it as an important driver of atherosclerotic plaque growth and show the potential of cell-type specific therapeutic intervention aimed at control of this disease.
Figure 2: FGF-TGFβ signaling in endothelial cells. In endothelial cells, inhibition of fibroblast growth factor (FGF) signaling leads to upregulation of TGFβ signaling activity. Activation of TGFβ signaling cascade induces endothelial cell to mesenchymal transition (EndMT), increases inflammation, permeability, and extracellular matrix (ECM) deposition, and therefore, accelerates atherosclerosis. Prolonged and/or extensive EndMT is clearly pathologic. Various studies demonstrated its occurrence in a number of disease settings including organ fibrosis, restenosis, transplant arteriopathy, vein graft remodeling, pulmonary hypertension, and cancer.
- Pulmonary hypertension (PH): Pulmonary vascular remodeling that occurs in PH is driven by the transformation of EndoMT, and augmented TGF-β signaling. Blocking this pathway reduces right ventricular systolic pressure, and right ventricular hypertrophy in treated mice.
- Cancer: Blocking TGF-β signaling in endothelial cells inhibits EndMT, which is a at the invasive front of tumors in melanoma and pancreatic cancer harboring mice. EndMT is a unique mechanism for the accumulation of carcinoma-associated fibroblasts.
- Transplant vasculopathy: EndMT is an important driver of neointima formation in a murine transplant arteriopathy model and in rejecting human transplants lesions.