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RNA splicing therapeutics for beta cell dysfunction and diabetes

Objective

Diabetes is a progressive metabolic disorder driven by beta cell dysfunction and failure, ultimately leading to chronic hyperglycemia and severe clinical complications. Current anti-diabetic treatments, including insulin secretagogues and incretin mimetics, primarily aim to control blood glucose levels without addressing the underlying molecular defects that drive beta cell decline, which in some cases even accelerate their exhaustion. Alternative splicing has recently emerged as a fundamental regulator of beta cell identity, glucose sensing, and insulin secretion, offering a novel therapeutic entry point. Our ERC-funded research uncovered a conserved program of islet-enriched microexons (IsletMICs), 3-51 nt exons controlling key genes in stimulus-secretion coupling. We have shown that splice-switching antisense oligonucleotides (SSOs) targeting specific IsletMICs can potentiate glucose-stimulated insulin secretion in human beta cells. This ERC PoC will advance a first-in-class RNA therapeutic for diabetes and other beta-cell related diseases through three integrated work packages: (1) develop a high-throughput screening pipeline to systematically test the effects of hundreds of SSOs on beta cell function; (2) targeted delivery using SSO-peptide conjugation and validation in primary human islets and hepatocytes for efficacy and toxicity in vitro studies; and (3) preclinical testing in a diabetic mouse model for biodistribution, safety, and glycemic control under a clinically relevant setting of beta cell dysfunction. By project completion, we will deliver a high-throughput platform for target discovery with subsequent decisive preclinical evidence, an optimised lead for selective beta cell delivery, and a roadmap for advancing into regulatory studies and engagement with pharmaceutical partners.

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Programme(s)

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Topic(s)

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Funding Scheme

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HORIZON-ERC-POC - HORIZON ERC Proof of Concept Grants

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Call for proposal

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(opens in new window) ERC-2025-POC

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Host institution

UNIVERSIDAD POMPEU FABRA
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 150 000,00
Address
PLACA DE LA MERCE, 10-12
08002 Barcelona
Spain

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Region
Este Cataluña Barcelona
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

No data

Beneficiaries (1)