WASHINGTON, Aug 2:
Scientists, including one of Indian-origin, have discovered a new molecular pathway responsible for causing heart failure and showed that a prototype drug blocks this pathway to protect the heart from damage.
In contrast to standard therapies for heart failure, the compound called JQ1 works directly within the cell’s command centre, or nucleus, to prevent damaging stress responses.
“Our discovery heralds a brand new class of drugs which work within the cell nucleus and offers promise to millions suffering from this common and lethal disease,” said Saptarsi Haldar, senior author on the paper, assistant professor of medicine at Case Western Reserve and cardiologist at University Hospitals Case Medical Center.
The researchers focused on the cell’s periphery to the nucleus – the very place that unleashes sweeping damage-control responses which, if left unchecked, ultimately destroy the heart.
They found that a new family of genes, called BET bromodomains, cause heart failure because they drive hyperactive stress responses in the nucleus.
Prior research linking BET bromodomains to cancer prompted the laboratory of James Bradner, the paper’s senior author and a researcher at the Dana-Farber Cancer Institute, to develop a direct-acting BET inhibitor, called JQ1.
In models of cancer, JQ1 functions to turn off key cancer-causing genes occasionally prompting cancer cells to “forget” they are cancer. In models of heart failure, JQ1 silences genetic actions causing enlargement of and damage to the heart – even in the face of overwhelming stress.
“While it’s been known for many years that the nucleus goes awry in heart failure, potential therapeutic targets residing in this part of the cell are often dubbed as ‘undruggable’ given their lack of pharmacological accessibility,” said Jonathan Brown, cardiologist at Brigham and Women’s Hospital and co-first author on the paper.
“Our work with JQ1 in pre-clinical models shows that this can be achieved successfully and safely,” he said.
Researchers studied mice who develop classic features of human heart failure and for a month administered a single daily dose of JQ1 to the sick animals.
The treated mice were protected from precipitous declines in heart function in a matter of days. Animals who received the compound saw a 60 per cent improvement, as compared to an untreated control group.
“Remarkably, at the end of the experiment, the hearts of many JQ1 treated mice appeared healthy and vigorous, despite being exposed to persistent and severe stress,” said Priti Anand, a researcher in Haldar’s lab and co-first author on the paper published in the journal Cell. (PTI)
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