Genetic and immunologic lung graft modulation during extended preservation.
Description: Lung transplantation (LTx) has poor survival compared to other organs, due to A/ Primary Graft Dysfunction (PGD) and B/ Rejection. Severe PGD presents as lung edema without treatment options. Normothermic ex-vivo lung perfusion (EVLP) maintains the isolated lung in a physiologic/metabolic state before implantation and is a unique treatment platform. With genetic modulation(CRISPR) we aim to silence PGD-genes during EVLP. Therefore, we administer an AAVvector that can introduce CRISPR-Cas9 in the lung cells. Aims: 1/ Validate a rat model of PGD after sequential EVLP+LTx. 2/ Observe transgene expression during rat EVLP+LTx with luciferase encoding AAVvector. 3/ Investigate if a CRISPR-Cas9 encoding AAVvector -targeted against a PGD-gene (e.g. IL-6)- can reduce PGD after rat EVLP+LTx. Rejection requires immunosuppression (IS) with known side-effects. (Pre)clinical heart/intestinalTx, showed that immunologic modulation can be induced by transfusion of donor-specific blood (DSBT). However, the mechanism is unclarified, neither investigated in LTx. First, we investigate the safety of DSBT in mice. Second, we analyze its effect on immune cells in a mice LTx. Third, we aim to explore optimal timing of DSBT and IS in mice LTx, mimicking the clinical setting to understand the IS effect on the tolerogenic potential of DSBT. CRISPR-therapy during rat EVLP+LTx and DSBT in mice LTx is uncharted territory. This project is ´an epic Odyssey´ paving the path towards clinical application.
Funder: Fonds Wetenschappelijk Onderzoek
Funding type: fellowship
Funder scheme: FWO fundamental clinical research fellowship
Start date: 2023-10-01
End date: 2028-09-30
Investigator: Laurens Ceulemans
Institution: KULeuven
Funded outputs count: 20
Funder award ID: 18E2B24N
OpenAlex ID: G2020110764