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Development of small molecule OGG1 Inhibitor and proof of concept in bleomycin-induced disease model of Inflammation and pulmonary Fibrosis

Project description

A molecular inhibitor against pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive condition characterised by pathological inflammation and scarring in the lungs. The causes of IPF are unknown, and there is no cure, with most patients surviving approximately three years after diagnosis. Scientists of the EU-funded DOIIF project had previously developed an inhibitor of the OGG1 enzyme, which is implicated in DNA repair during oxidative stress. Since inhibition of OGG1 seems to reduce inflammation and fibrosis and slow down IPF, researchers aim to take a lead compound through preclinical development and clinical phase 1/2a for further commercialisation.

Objective

Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases where
Idiopathic Pulmonary Fibrosis (IPF) is one of the most severe diseases. IPF is a progressive condition with unknown etiology and a median
survival of three years from diagnosis. Current medical treatment is limited to slowing down the disease and thus there is still a high unmet medical need. OGG1 enzyme has a major role in DNA repair in conditions of oxidative stress and also in regulation of gene transcription involved in immune responses. In our ERC grant we developed a first-in class OGG1 inhibitor that protects from exaggerated immune response induced by the proinflammatory mediator TNFα. We have shown with this compound in
several airway inflammation models, that inhibition of OGG1 results in a significant down regulation of mediators associated with inflammation and fibrosis, reduced infiltration of immune cells in lungs and increased alveolar integrity compared with control. We have developed a large number of compounds and in this proposal we aim to demonstrate proof of concept (PoC) for the most promising compound in an established model of pulmonary fibrotic diseases in order to select a candidate drug (CD). Our plan is to establish collaboration with industrial partners for further development in order take one compound through preclinical development and clinical phase 1/2a for further commercialization. Treatment with a potent OGG1 inhibitor has the potential to attenuate or resolve the progress of the disease, alone or in combination with existing therapies and increase survival of IPF patients and reduce healthcare costs.

Host institution

KAROLINSKA INSTITUTET
Net EU contribution
€ 150 000,00
Address
Nobels Vag 5
17177 Stockholm
Sweden

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Region
Östra Sverige Stockholm Stockholms län
Activity type
Higher or Secondary Education Establishments
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Total cost
No data

Beneficiaries (1)