PureTech Announces Publication of New Preclinical Research from Collaborators that Supports Mesenteric Lymphatic Dysfunction as a Potential Cause of and Therapeutic Target for Obesity and Insulin Resistance - Seite 2

The study also found that inhibition of COX-2 and VEGF-C signaling within the mesenteric lymphatics resulted in a repatterning of the lymphatic vasculature, which in turn led to reduced branching and significantly less leakage of lymphatic fluids rich in lipids and pro-inflammatory mediators. Additionally, targeted inhibition of COX-2 function with a celecoxib prodrug developed using PureTech’s lymphatic targeting Glyph technology platform led to a normalization of multiple biomarkers, including VEGF-C concentrations specifically within mesenteric lymph and surrounding adipose tissue, and to levels observed in control animals that were not fed a high-fat diet. This correlated with reduced lymphatic vessel branching and leakage as well as restoration of glycemic control, and weight gain was blocked in the animals fed a high-fat diet. In fact, targeted administration of the celecoxib Glyph prodrug led to a 10-fold greater uptake of celecoxib in mesenteric lymph and more effective restoration of lymphatic function and glycemic control compared to the administration of unmodified celecoxib, which is commercially available.

“What’s remarkable about this study is that the COX-2 inhibitor was able to meaningfully repattern the chaotic lymphatic structure in obese mice when it was delivered directly to the mesenteric lymphatics with our Glyph technology platform, and that repatterning was accompanied by a substantial decrease in both weight gain and insulin resistance,” said Joseph Bolen, Ph.D., Chief Scientific Officer at PureTech. “We are excited to continue to build off of this pioneering research to identify and advance new potential treatment applications of this platform.”

About the Glyph Technology Platform

Glyph is PureTech’s synthetic lymphatic-targeting chemistry platform which is designed to employ the body’s natural lipid absorption and transport process to orally administer drugs via the lymphatic system. PureTech believes this technology has the potential to (1) enable direct modulation of the immune system via drug targets present in mesenteric lymph nodes and (2) provide a broadly applicable means of enhancing the bioavailability of orally administered drugs that would otherwise become inactive by first-pass liver metabolism. PureTech has demonstrated proof-of-concept by achieving therapeutically relevant plasma levels following oral administration of a neurosteroid, allopregnanolone, in small animal and non-human primate model systems. This and other work has resulted in the generation of PureTech’s lead Glyph product candidate, LYT-300 (oral allopregnanolone), which is expected to enter a clinical trial by the end of 2021. The Glyph technology platform is based on the pioneering research of Christopher Porter, Ph.D., and his team at the Monash Institute of Pharmaceutical Sciences at Monash University in Melbourne, which PureTech has exclusively licensed.