Therapeutic efficacy of antisense oligonucleotides targeting PHLPP in preclinical models of diabetes

• Applicant: Amin Ardestani, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 498542712

Both type 1 diabetes (T1D) and type 2 diabetes (T2D), highly complex in their pathophysiology, finally result from pancreatic beta cell failure; hallmark and fundamental cause of diabetes. Underlying molecular mechanisms are still not fully characterized in order to provide beta cell specific therapies for a cure. The modulation of the survival of highly functional beta cells and/or enhancement of beta cell regenerative capacity therefore represent an attractive therapeutic approach for diabetes. Serine-threonine phosphatases (STPs) such as PHLPP1/2 (PH domain leucine-rich repeat protein phosphatase-1/2) regulate cell survival and serve as potential targets for drug development. Our understanding of the function and mechanism of PHLPPs in beta cell death regulation has important biological and clinical significance. We have identified that PHLPPs levels were highly elevated in metabolically stressed human and rodent diabetic β-cells. Genetic inhibition of PHLPPs markedly improved beta cell survival and function in experimental models of diabetes in vitro, in vivo and in islets from patients with T2D, presenting PHLPPs as promising targets for functional regenerative therapy of pancreatic beta cells in diabetes. With the aim of therapeutically inhibiting PHLPPs in a beta cell specific manner, this project will exploit a novel strategy of ligand-induced internalization of the glucagon-like peptide-1 receptor (GLP1R) to deliver PHLPP antisense oligonucleotides (PHLPP-ASOs) potently and specifically to pancreatic beta cells by conjugating them to a GLP1R peptide agonist. We will test GLP1-PHLPP-ASOs for their ability to restore beta cell survival and function and to normalize glycemia in vitro und in vivo. Also, we will identify the regulatory networks of direct or indirect PHLPP-driven transcriptional gene regulation in PHLPP-depleted β-cells at the bulk (whole islets) and single cell level (beta cells/endocrine cells) by using RNA-sequencing. This will help us to further characterize potential functional metabolic, proliferative and survival pathways with major focus on beta cell survival signaling such as mTOR, Hippo, AKT and OXPHOS. The purpose of this proposal is to move forward our initial highly promising results into translational research; to establish the previously uncharacterized PHLPP1/2 signaling pathway as a novel target for curative pharmacological intervention to restore functional pancreatic beta cells and normoglycemia in diabetes.

• DFG Programme: Research Grants
• International Connection: United Kingdom