Monash University researchers have revealed a novel therapy that corrects the mechanism in the body that's gone wrong in Postural Orthostatic Tachycardia Syndrome (POTS), the condition affecting the former lead singer of The Wiggles.
Central Clinical School (CCS) researchers led by Professor Sam El-Osta found how genes that protect against POTS become silent or ‘switched off’ – and identified a drug to switch them on again.
POTS is one of a group of disorders that have orthostatic intolerance as their primary symptom, in which a greatly reduced volume of blood returns to the heart after the person stands up from a lying-down position. The main symptom of POTS is fainting. Other symptoms include feeling light-headed, fatigue, sweating, shortness of breath and in some cases chest pain and heart palpitations.
In Australia, POTS has become referred to as ‘Wiggles Disease’ after Greg Page AM retired from the popular children's music group in late 2006 after developing the condition. The ‘Yellow Wiggle’ recently suffered a heart attack at a charity concert in Sydney likely to be a complication of POTS.
Professor El-Osta said that while the gene implicated in POTS – norepinephrine transporter (NET) – had been known for several decades, past research had failed to find a genetic mutation responsible for the symptoms.
The study, published today in the highly regarded American Heart Association journal Circulation Research, revealed that the enzyme EZH2 is responsible for silencing this gene.
“We predicted that inhibiting this epigenetic condition could reactivate NET gene function and used a pharmacological drug called GSK-126 that could specifically inhibit EZH2 activity with dramatic results,” he said. “This is the first description of NET reactivation using a drug. The beauty is that it allows us to target very specifically the enzyme to reactivate gene function.”
Currently, there is no specific pharmacological treatment available for POTS, which affects mainly people aged 18 to 50 years, eighty percent of whom are women. “We’re far from it now and clinical trials would need to be conducted but the new drug could lead to better management of POTS,” he said.
Professor El-Osta’s team conducted ex vivo studies isolating blood cells from patients with POTS who failed to respond to current treatments and cells from healthy donors. He said the sample group was relatively small. “Ideally, we’d like to see the work expanded in Australia and overseas and to have our findings validated.”
First author on the study was Dr Harikrishnan Kaipananickal from Professor El-Osta’s Epigenetics in Human Health and Disease Laboratory.
Reference: Kaipananickal, et al. (2020) Targeting Treatment Refractory NET by EZH2 Inhibition in Postural Tachycardia Syndrome. Circulation Research DOI: https://dx.doi.org/10.1161/CIRCRESAHA.119.315654
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