Adiponectin (Adpn), an adipokine which displays insulin-sensitive properties, is a very promising target to tackle the cardiometabolic complications associated with Type 2 Diabetes (T2D). Design of Adpn-mimicking drugs has been so far hampered by the difficulties encountered to produce this therapeutic agent in its native oligomerized active forms. The scientific basis of EVADIPO relates to partner 1’s data (Coordinator: S Le Lay, Inserm UMR1087, Institut du Thorax, Nantes) that demonstrate that adipose tissue (AT)-derived extracellular vesicles (EVs) are highly enriched in adiponectin oligomers. This vesicular Adpn mainly distributes at the EV surface and its quantity is highly dependent on patient/animal adiponectinemia. Of interest, EV-associated Adpn is more stable than soluble Adpn in plasma and maintains its insulin-sensitive properties in vitro and in vivo. Thus, AT-derived Adpn-enriched EVs are indeed able to reverse insulin-resistance of obese mice, by contrast to EVs devoid of any Adpn.
EVADIPO aims to develop an innovative pharmacological approach based on EV-based delivery to provide metabolic active forms of Adpn. Our project relies on an academic Inserm UMR1087/Ciloa (industrial) partnership which aims to refine the production of EVs carrying Adpn and to establish the proof of concept of the therapeutic potential of these vesicles on T2D in order to pave its clinical development by adapting the production of EVs to “GMP-like” quality standards, suitable for preclinical studies.
Our objectives divided in four "work-packages", will be moreover framed by a work-package dedicated to the management and coordination of EVADIPO:
WP1- Customize Adpn-enriched EVs (Adpn+ EVs) based on the industrial partnership with Ciloa, that has patented a technology using a pilot peptide (PP) allowing the efficient targeting of Adpn to EV membrane. On the basis of functional cellular assays, the chimeric construct(s) allowing the production of Adpn+ EVs inducing the most potent insulin-sensitizing effects will be retained.
WP2- Reveal the therapeutic potential of Adpn+ EVs by studying their ability to counteract the cardiometabolic alterations associated with T2D. The therapeutic dose of Adpn+ EVs, as well as their delivery, will be optimized before exploring their beneficial cardiometabolic outcomes in diabetic mice models presenting advanced cardiometabolic complications (obese high fat diet mice and lipodystrophic mice invalidated for seipin).
WP3- Unravel the molecular mechanisms underlying the insulin-sensitizing effects of Adpn+ EVs by exploring their biodistribution, kinetics, interaction and downstream signaling pathways in relevant cellular models.
WP4- Optimize the production of large quantities of Adpn+ EVs to “GMP-like” high quality grade standards in order to pave the way for their future therapeutic development.
Our bipartite-partnership associating complementary skills on T2D pathophysiology and EV surface functionalization strategies will bring the proof of concept of the therapeutic potential of Adpn+ EVs for diabetic patients.
Madame Soazig LE LAY (L'unité de recherche de l'institut du thorax)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Institut du thorax L'unité de recherche de l'institut du thorax
Help of the ANR 385,485 euros
Beginning and duration of the scientific project: September 2022 - 36 Months