30th May, 2023 – New Research by the HCI on Cardioprotection Published in Nature

In new research published this week in the prestigious journal Nature, The Hatter Cardiovascular Institute at UCL has demonstrated that a new drug called UCL-TRO-1938 is able to protect the heart from injury in experimental models of heart attack. UCL-TRO-1938 was developed as part of a large collaboration with colleagues at UCL, Cambridge University, and elsewhere, as a drug able to directly activate the PI3K∝ isoform associated with the RISK pathway. The RISK pathway (or “Reperfusion Injury Salvage Kinase pathway”) first described by Prof Derek Yellon, Director of the Hatter Cardiovascular Institute,  is an important pro-survival signalling pathway capable of protecting the heart from injury. Prof Yellon, Prof Davidson, and researchers at the Institute are now extending their studies to evaluate whether UCL-TRO-1938 might also be beneficial in related diseases where there is organ damage due to blockage in blood supply, such as ischaemic stroke.

When a patient arrives at hospital with an acute myocardial infarction (heart attack) the first thing that needs to occur is for the immediate removal of the clot in the coronary and the rapid re-establishment of coronary artery blood flow (termed reperfusion). However, the process of reperfusion itself comes at a price in what has been termed “reperfusion-induced injury”. As such designing drugs to prevent reperfusion-induced injury has been the goal of basic & clinical scientists for many years. The British Heart Foundation has supported the research undertaken in the Hatter Cardiovascular Institute at UCL for over 20 years and could now be rewarded with the identification of this new compound, UCL-TRO-1938, which can protect the heart from injury following a heart attack.

The research within the Hatter Cardiovascular Institute at UCL, led by Prof Derek Yellon, has focused on the ability to activate pro-survival pathways in the cell, which can subsequently protect the muscle following a myocardial infarction or heart attack. This, pro-survival signalling pathway, was initially proposed by researchers at the Hatter Cardiovascular Institute in 2002 and called the “RISK pathway”.  Numerous studies were subsequently undertaken to demonstrate the ability of this pathway to protect the heart as well as investigate its downstream targets. This was followed by assessing which specific subtype or isoform of the PI3 Kinase pathway would offer the most protection.

Scientists within the Hatter Cardiovascular Institute undertook a range of fundamental studies and discovered that the alpha isoform of PI3 Kinase appeared to be the one that offered the most promise. As such, in a collaboration with the Cancer Institute at UCL, AstraZeneca (in their open innovation programme) and UCL’s Drug discovery group they developed a new compound which specifically activates the PI3K∝ isoform. This compound, UCL-TRO-1938, has been shown in experimental studies to protect the heart from ischaemia-reperfusion injury as well as enhance nerve regeneration and could lead to this class of drugs and therapies being used for a wide range of conditions.

Read our new Nature paper on the UCL-TRO-1938 compound here.

For further background, our recent review summarizing more than 3 decades of research in the field of cardioprotection that have highlighted the significance of the RISK pathway in the treatment of Ischaemic Reperfusion Injury can be read here.