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Synthetic modified mRNA administration in a first in-human ex-situ heart failure model validates its use as a novel, effective and safe method of evaluating drug exposure and efficacy.

J O Louca(1) M Althage(2) M Öchsner(1) A Page(3) J P Nunes(3) C Wilson(1) S Sinha(1) S Messer(4) J M Bae(1) M Hu(1) N Asemota(1) N Henderson(2) J Lindquist(2) D Spater(2) A Collén(2) K Sengupta(2) B Challis(2) S Large(3)

1:University of Cambridge; 2:AstraZeneca; 3:The Royal Papworth Hospital; 4:The Golden Jubilee National Hospital

Modified mRNAs hold great promise for treating a wide variety of illnesses, but as of yet are not routinely used in cardiovascular medicine.

We utilized a novel modRNA in explanted recipient human hearts from transplantation to test whether it was expressed in a human model of cardiomyopathy. The modRNA was injected directly into the myocardium of explanted recipient hearts from transplantation. Two doses were injected at different sites – 1mg (high-dose) and 0.1mg (low-dose). The hearts were perfused ex-situ for 6 hours using our novel perfusion machine – the multi-organ perfuser (m0rgan). Perfusion was carried out at normothermic conditions. Expression of this mRNA was assessed after 6 hours of perfusion by mesoscale immunoassay analysis.

There were elevated levels of the protein in the subendocardium and mid-myocardium of injection sites which received our novel mRNA. Low dose mRNA resulted in an increase in protein levels in the mid-myocardium and subendocardium. High-dose mRNA resulted in significantly elevated protein levels in the subendocardium.

This study demonstrates the utility of ex-situ perfusion of explanted diseased organs from transplant recipients as a model to test novel therapeutics. It offers the ability to test therapies before clinical trials in human tissues in a safe manner. Moreover, it enables efficacy and dosing to be assessed before the clinical trial stage. We propose that this model acts as a link between preclinical and clinical studies for potential therapeutics.

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