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Stratified Therapeutic Assessment Platform for Short Telomere related Lung Fibro...

Stratified Therapeutic Assessment Platform for Short Telomere related Lung Fibrosis using Patient-Derived iPSC Idiopathic pulmonary fibrosis (IPF) is a lethal scarring lung disease often leading to death within 3 years of diagnosis. New antifibrotic medications slow disease progression but they are poorly tolerated by patients. Telomeres,... ver más

30/09/2028

ROYAL COLLEGE OF S...

1M€

Presupuesto del proyecto: 1M€

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ROYAL COLLEGE OF SURGEONS IN IRELAND No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-10-01

ERC-2022-STG: ERC STARTING GRANTS Scope:Objectives

I+D

Cerrada hace 3 años

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Duración del proyecto: 59 meses Fecha Inicio: 2023-10-01
Fecha Fin: 2028-09-30

Líder del proyecto

ROYAL COLLEGE OF SURGEONS IN IRELAND No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 1M€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto Idiopathic pulmonary fibrosis (IPF) is a lethal scarring lung disease often leading to death within 3 years of diagnosis. New antifibrotic medications slow disease progression but they are poorly tolerated by patients. Telomeres, protective structures or caps at the ends of chromosomes, governed by the enzyme telomerase are shortened in type 2 alveolar epithelial cells (AT2)s in sporadic IPF but particularly so in inherited mutations of telomere related genes causing severe disease with early onset. Early clinical studies indicate that danazol modulates telomere length and prevents the progression of pulmonary fibrosis but it is poorly tolerated by patients, causing liver toxicity. Gene therapies including mRNAs which target telomerase have potential but human preclinical models do not exist to test their efficacy. Thus, a new human preclinical model is required to better understand pathogenesis and find new treatments. In preliminary work, I demonstrate that AT2 cells generated from patient-iPSC (iAT2) can replicate elements of pulmonary fibrosis pathogenesis and that telomere length in these cells undergoes heterogenous shortening over time, analogous to the shortening which occurs in vivo. Based on this data and previously published mouse studies, I hypothesise that telomere shortening in AT2 cells causes senescence, DNA damage and inflammation in both sporadic and inherited forms of IPF. Furthermore, I hypothesise that specific gene stratified mRNA-nanomedicines delivered to the lung can modulate telomere length in a precise manner avoiding toxicity. I will compare iAT2 and hepatic cells generated from patients recruited to a clinical trial of danazol to their own clinical outcomes from the study, thereby performing the first ‘clinical trial in a dish’ in pulmonary fibrosis - to a) better understand the role of telomere shortening in IPF and to b) identify and test gene stratified mRNA-nanomedicines and delivery chemistries leading to improved patient survival.

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