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Pei-Yu Chen, BS, MS, PhD, Senior Research Scientist, Cardiovascular Medicine, at Yale University, has been awarded a two-year grant through the Vasculitis Foundation’s Young Investigator’s Award Program for her study, “siRNA Nanoparticle Targeting Endothelial Cell TGFβ Signaling Against ANCA-Vasculitis.” The aim is to reveal how large a role TGFβ-mediated EndMT plays as drivers of TGFβ vasculitis. By targeting TGFβ and reducing TGFβ-mediated EndMT, the hope is to decrease blood vessel inflammation, slow down vasculitis progression, and restore vascular normalcy.
Inflammation is part of the body’s natural healing system that is vital in fighting injury and infection. It’s also a key contributor to many vascular diseases and can cause the blood vessels to swell, narrow and become blocked. Behind many inflammatory vascular diseases are unhealthy endothelial cells (the inner lining of blood vessels). “Our team recently showed that the gain of TGFβ activity causes healthy endothelial cells to lose their distinctive characteristics, which leads to increased inflammatory response and scarring in the blood vessels,” Dr. Chen explained. “Since vasculitis is an inflammatory process that affects all sizes of blood vessels in the body, we are investigating the potential benefits of decreasing TGFβ activity in endothelial cells in vasculitis.”
Vascular endothelial cells are very vulnerable to high TGFβ activity. As TGFβ activity levels rise, endothelial cells can turn into different cell types, a process called endothelial to mesenchymal transition (EndMT). EndMT is thought to contribute to inflammation in blood vessels, but it’s not fully understood how it works or its relationship to vasculitis. However, studying the connection between TGFβ-mediated EndMT and vasculitis could help researchers better understand the disease.
While vascular inflammation is the leading cause of vasculitis, no existing pharmaceutical treatments have been successful in reversing the later phase of chronic vascular inflammation. “Therefore, there is an unmet medical need to develop novel treatment for people suffering from vasculitis,” Dr. Chen said. “With our new drug designed to target ‘specific cell type’ and ’specific mRNA,’ we now have the potential to develop therapeutics for a wide range of diseases associated with chronic vascular inflammation including vasculitis.”
Many diseases are caused by misbehaving proteins (too much/too little or the same amount but too high/too low activity) and inhibiting or blocking a misbehaving protein’s production is a great treatment approach that can be achieved using siRNA, which can delete specific disease-causing mRNA before they are made into a protein.
Researchers and drug companies worldwide have developed various ways to block TGFβ activity, which plays a role in many human diseases. However, while blocking TGFβ activity has shown promise in lab studies, none of the drugs have been approved for clinical use due to concerns about their effectiveness and safety. The main issue is that TGFβ has different effects depending on the type of cell and situation. Although siRNA is a powerful therapeutic tool, delivering it to cells can be challenging because it breaks down easily. “To address this, we’ve developed a protective coating called a lipid nanoparticle (LNP) that can deliver siRNA specifically to endothelial cells. By using this approach to reduce TGFβ activity only in endothelial cells, we can avoid the toxicity side effects of global TGFβ inhibition observed in other studies. This could lead to new treatments for vascular inflammatory diseases,” Dr. Chen said.
Lingfeng Qin, MD, PhD, is co-principal investigator in this study, and has been her research partner for more than 10 years. Dr. Qin specializes in surgical procedures and performs surgery to treat vascular disease.
LNP-based drug delivery is the beginning of a new and exciting generation of therapeutics. This technology can be applied to different siRNA or mRNA drugs for the treatment of various human diseases. Over the last few years, LNP-based RNA vaccines for COVID-19 have been administered to hundreds of millions of people. “Based on our pre-clinical results establishing proof-of-concept, we have great enthusiasm for our LNP-siTGFβ potential as a novel therapy for patients with vasculitis, and we expect it to find more useful utilities in the future,” Dr. Chen said.
Transforming growth factor beta (TGFβ): named for the function it was originally discovered to perform—making healthy cells into aggressively growing malignant (cancer) cells, but researchers have discovered that TGFβ is a multifunctional secreted small protein.
messenger RNA (mRNA): a molecule that contains the instructions that directs the cells to make proteins, building blocks to support structure, function, and repair organs inside the human body.
Small interference RNA (siRNA): belong to a new class of drugs that work inside the cell. They bond to their specific target mRNA, recruit cellular proteins that cut the targeted mRNA, which is then degraded before the targeted mRNA can produce the disease-causing proteins.