‘Thousands of things change in the body during a heightened immune response,’ James says. ‘We used the organoids to screen these changes and find out which inflammatory factors cause the heart damage. Importantly that meant we could precisely pinpoint how to stop it as well.’
During a heightened immune system response to COVID-19, the immune system triggers a cytokine-storm. Cytokines are a diverse family of molecules that defend the body against pathogens like the virus. They act like messengers by signalling to cells to change their functions.
James screened cytokines and other molecules that are elevated in COVID-19 patients. He found 2 cytokines and a molecule associated with viral infection cause the heart damage observed in COVID-19 patients. He termed this a cardiac cytokine storm.
Finding the drug target
James’s team then searched in heart cells for the sites that the cardiac cytokine storm induces to change. They did this using phosphoproteomics. This method finds sites of phosphorylation, a key biochemical signature of signalling.
‘Phosphorylation is one of the most used processes in a cell for signalling,’ James notes. ‘It indicates which signalling pathway is activated. The team found phosphorylation sites on bromodomain-containing proteins (BRDs).
James decided to target the BRDs with drugs because drug inhibitors for BRDs already existed. These drugs are called bromodomain extraterminal inhibitor (BETi) drugs.
The team hoped to prevent the cardiac cytokine storm from damaging the heart by using BETi drugs to stop BRDs changing their functions.
Screening existing drugs
The team screened all the BETi drugs that have been tested in clinical trials for cancer and chronic diseases. They found that the drug INCB054329 reversed common COVID-19 heart damage in organoids and mouse hearts. But this drug has significant side effects.
The BETi drug apabetalone also prevented COVID-19 heart damage. It has a more selective binding to the BRDs which limits side effects. The team concluded apabetalone is a lead candidate to prevent COVID-19 damage to the heart.
The pharmaceutical company that owns apabetalone had supplied the drug to James’s team for the tests. Based on the positive results, the company began phase II clinical trials to test the drug in hospitalised COVID-19 patients. They aim to gain regulatory approval to use apabetalone to protect COVID-19 patients and their hearts.
Next generation drugs
‘Even though we discovered this treatment pathway as part of a COVID 19 project, it has broad implications for heart failure in general and that’s what we’re exploring now,’ James tells us. ‘This pathway could be really important.’
‘In heart failure, heart cells have suboptimal performance. The heart might have lost some cells after a heart attack, or you might have high blood pressure or diabetes. These insults cause pathological signalling which can be detrimental to heart function.’
James’s COVID-19 research showed that blocking that signalling process allows the heart cells to perform optimally while the insults are still there. He aims to develop next generation drugs to block other pathological signals to the heart cells. This could be a new way of treating heart failure.
‘We want the next generation drugs in this class to be developed by us here in Queensland,’ James says.
The greatest moment of James’s career
‘This project is probably the greatest moment of my career because we discovered something really important,’ James continues. ‘We had no idea that was going to happen. Traditionally, it takes years to get from basic research to a clinical trial. Seeing that translation in such a rapid time frame proves our approach using the organoids works.’
