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
20 Septembre 2021 - 5:04PM
Business Wire
Dysfunction of the mesenteric lymphatics and
leakage of pro-inflammatory lymph fluids promoted the accumulation
of visceral adipose tissue and insulin resistance in a preclinical
model
Treatment with a lymph-targeted COX-2 inhibitor
using PureTech’s GlyphTM technology platform normalized lymphatic
vasculature, blocked weight gain and reversed glucose intolerance
and hyperinsulinemia
PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) ("PureTech" or the
"Company"), a clinical-stage biotherapeutics company dedicated to
discovering, developing and commercializing highly differentiated
medicines for devastating diseases, today announced the publication
of a research paper in Nature
Metabolism, which showed for the first time that restoring
normal function of the mesenteric lymphatics may reverse insulin
resistance and modify obesity-associated metabolic disease. Results
from the preclinical study provide further support for the
therapeutic potential of PureTech’s Glyph technology platform,
which is designed to enable the trafficking of small molecule drugs
directly into the mesenteric lymphatic system following oral
administration. The groundbreaking study was led by PureTech
collaborators Natalie Trevaskis, Ph.D., Associate Professor at the
Monash Institute of Pharmaceutical Sciences (MIPS) in Australia,
Christopher Porter, Ph.D., MIPS Director, and Enyuan Cao, Ph.D.,
Post-Doctoral Research Fellow at MIPS, in collaboration with
PureTech scientists.
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PureTech Health today announced the
publication of a research paper in Nature Metabolism using its
Glyph technology platform that showed - for the first time - that
mesenteric lymphatic dysfunction may be a potential cause of and
therapeutic target for obesity and insulin resistance. (Graphic:
Business Wire)
The work demonstrates that obesity may be associated with
profound and progressive dysfunction of the mesenteric lymphatic
system. As shown in preclinical models, a high-fat diet stimulated
the formation of new lymphatic vessels, which grew in a highly
disorganized pattern. These tortuous, branching vessels tended to
leak lymphatic fluid rich in lipid metabolites and pro-inflammatory
mediators into the visceral adipose tissue in the abdomen,
triggering the promotion of insulin resistance. Results from ex
vivo experiments using clinical samples suggest that these
observations may extend to humans as well.
“We have known for years that the accumulation of fat around the
abdomen is correlated with higher rates of diabetes, but the
biological reasons remained unclear. This is the first study to
identify the profoundly damaging cycle in which the accumulation of
abdominal fat leads to dysfunction of the mesenteric lymphatics,
which in turn promotes more fat deposition and insulin resistance,”
said Dr. Trevaskis. “Most exciting of all, we have preclinical
evidence that intervening in this cycle by inhibiting the pathways
associated with the lymphatic dysfunction may be a treatment for
both obesity and associated metabolic disease. We believe that
PureTech’s Glyph technology platform is key to this intervention,
because it traffics the inhibitors directly where they are needed
in the mesenteric lymphatics.”
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.
About PureTech Health
PureTech is a clinical-stage biotherapeutics company dedicated
to discovering, developing and commercializing highly
differentiated medicines for devastating diseases, including
inflammatory, fibrotic and immunological conditions, intractable
cancers, lymphatic and gastrointestinal diseases and neurological
and neuropsychological disorders, among others. The Company has
created a broad and deep pipeline through the expertise of its
experienced research and development team and its extensive network
of scientists, clinicians and industry leaders. This pipeline,
which is being advanced both internally and through PureTech's
Founded Entities, is comprised of 25 therapeutics and therapeutic
candidates, including two that have received both U.S. FDA
clearance and European marketing authorization, as of the date of
PureTech's most recently filed Half Year Report and corresponding
Form 6-K. All of the underlying programs and platforms that
resulted in this pipeline of therapeutic candidates were initially
identified or discovered and then advanced by the PureTech team
through key validation points based on the Company's unique
insights into the biology of the brain, immune and gut, or BIG,
systems and the interface between those systems, referred to as the
BIG Axis.
For more information, visit www.puretechhealth.com or connect
with us on Twitter @puretechh
Cautionary Note Regarding Forward-Looking Statements
This press release contains statements that are or may be
forward-looking statements, including statements that relate to our
expectations regarding the Glyph™ technology platform including the
potential for new treatment applications, the applicability of
preclinical results to human subjects, and the timing of LYT-300 to
enter a clinical trial, our product candidates and approach towards
addressing major diseases, and our future prospects, developments,
and strategies. The forward-looking statements are based on current
expectations and are subject to known and unknown risks and
uncertainties that could cause actual results, performance and
achievements to differ materially from current expectations,
including, but not limited to, those risks and uncertainties
described in the risk factors included in the regulatory filings
for PureTech Health plc. These forward-looking statements are based
on assumptions regarding the present and future business strategies
of the Company and the environment in which it will operate in the
future. Each forward-looking statement speaks only as at the date
of this press release. Except as required by law and regulatory
requirements, neither the Company nor any other party intends to
update or revise these forward-looking statements, whether as a
result of new information, future events or otherwise.
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Investors Allison Mead Talbot +1 617 651 3156
amt@puretechhealth.com U.S. media Nichole Sarkis +1 774 278
8273 nichole@tenbridgecommunications.com
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