Research

Our collaborative team investigates the epigenetic mechanisms underlying vascular stenosis and retinal disease and also develops lesion-targeting nanobased therapeutic delivery strategies, in close partnership with Dr. Craig Kent, MD, at the University of Virginia and Dr. Shaoqin Gong, PhD, at the University of Wisconsin–Madison.

1. Targeting epigenetic “writer” DOT1L via epiNanopaint to treat vascular stenotic disease.

Each year, over a million Americans receive open vascular reconstructions to restore blood flow to vital organs, such as bypass vein grafting on the heart to avoid heart failure. Unfortunately, the grafts fail at high rates, and there are no FDA-approved methods to prevent graft failure. We seek to tackle this problem using a two-pronged approach. We determine the potential of DOT1L as a therapeutic target for treating graft stenosis or narrowing. We also develop the epiNanopaint technology to deliver DOT1L-inhibiting drugs locally and sustainably by “painting” bioadhesive nanoparticles on vein grafts. This straight-forward method could be broadly applicable to other open vascular reconstructions including AV-fistula, the vascular access for renal dialysis.

2. Developing targeted approaches to treat abdominal aortic aneurysm (AAA).

AAA is a balloon-like bulge of the aorta, the largest artery in the body. A silent killer, AAA typically grows without symptoms, but can suddenly rupture, leading to mortality rates of 70% to 90%. Currently, effective medical therapy for AAA is lacking, primarily due to gaps in the understanding of the disease mechanisms and limitations in targeted drug delivery methods. We propose that targeting the overactivity of epigenetic “readers”—identified as the Achilles’ heel—could effectively avert aberrant pro-AAA gene activities. Our strategies involve using small molecules to evict overactive readers from the epigenomic landscape, or reducing their proteins through PROTAC technology, akin to demolishing a skyscraper in Manhattan. These agents could be precisely delivered using AAA-targeting, biomimetic, injectable nanoparticles. Success in this endeavor could mark a major breakthrough in developing the first medicinal therapy for AAA.

3. Targeting cellular stress response for treating aortic aneurysm.

Our team has pinpointed PERK, a signaling protein central to the cellular stress response, as a potential target. We aim to uncover the mechanisms underlying aneurysms and devise a precise drug delivery system involving bio-camouflaged nanoclusters, likened to a cluster bomb. “Detonated” at the disease site, these nanoclusters disperse smaller drug-loaded nanoparticles, facilitating efficient penetration into the aneurysmal tissues. This precision-targeting strategy holds potential for minimizing systemic side effects, while maximizing therapeutic efficacy of aneurysm treatments.

4. Biomimetic torpedoes for stent-free local drug delivery to treat restenosis.

Current treatments for cardiovascular disease often rely on drug-eluting stents implanted post-angioplasty. However, this procedure can inadvertently cause problems like in-stent restenosis and thrombosis. Angioplasty and stenting mechanically damage the inner lining of arteries, leading to the formation of neointimal lesion and thrombi, exacerbating restenosis. To tackle this challenge, our team has pioneered a biomimetic “torpedo” system. The targeted gene therapy leverages cell membrane capsules adorned with lesion-specific peptides for accurate delivery. Moreover, the torpedo carries siRNAs that specifically target a driver of restenosis that governs multiple pathways including epigenetic remodeling. Thereby, the torpedo offers a triple-targeting approach.

5. Sigma receptors in retinal degeneration and protection.

Retinal degeneration leads to vision impairment and blindness. The disease mechanisms are still poorly understood, limiting the development of effective therapies. The structurally and genetically distinct sigma-1 receptor and sigma-2 receptor (or TMEM97) comprise a unique class of drug binding sites. Their variants are associated with major human neuronal diseases. We are studying their epigenetic regulations and their potential as therapeutic targets for treating retinal degeneration and other neurodegenerative diseases.