Epigenetic targeting and nanoplatform-enabled local drug delivery - a two-pronged approach to stenosis prevention after vascular surgery - Project Summary Each year, millions of patients worldwide receive open vascular reconstructions (such as bypass vein grafting) to treat occlusive cardiovascular diseases. Unfortunately, post-surgery failure, primarily due to lumen-narrowing neointimal hyperplasia (IH), occurs at unacceptably high rates leading to tremendous human and financial costs. IH is formed primarily by the vascular smooth muscle cells (SMCs) that undergo phenotypic transition, with dysregulated epigenetic remodeling now recognized as a root problem. We have obtained promising data to show that DOT1L (disruptor of telomeric silencing 1-like), an epigenetic histone code writer, is a potential master target for IH mitigation. DOT1L is upregulated in human IH tissues. Pharmacologic inhibition and molecular silencing of DOT1L mitigated SMC phenotypic transition and abated IH in animal models. We generated SMC- specific DOT1L knockout mice and found that the absence of DOT1L in SMCs inhibited the development of IH. Toward translation of the basic findings with DOT1L into human applications, we designed a prototype nano- platform called Epi^NanoPaint for sustained drug delivery that is tailored for open vascular reconstructions. When used to deliver the DOT1L-selective inhibitor, Pinometostat, Epi^NanoPaint mitigated IH in obese Zucker rats following vein grafting. These findings support the premise that DOT1L is a master pathogenic target that dictates SMC phenotypic transition and IH progression. In Aim 1, we will focus on dissecting the physiology of DOT1L in modulating SMC function associated with IH using our novel mouse models. We will also delineate the mechanism behind the epigenetic role of DOT1L in controlling IH using a combination of epigenomic, transcriptomic, and biochemical assays. In Aim 2, we will optimize the Epi^NanoPaint platform to achieve safe and effective delivery of therapeutic reagents for open vascular surgery application. We will then conduct pre- clinical studies to establish the risk-benefits of the selected Epi^NanoPaint product to treat IH using animal models of vein grafting. This project is innovative, as it will advance understanding of DOT1L’s role as an epigenetic determinant of IH, and also develop a therapeutic prototype conveniently suitable for open vascular reconstructions.
