8 Feb 2017

Designer molecule could treat blood clotting without excessive bleeding

Christoph Hagemeyer's Nanobiotechnology group has a number of authors (bolded) on the JAHA paper: L-R Ms Shweta Jagdale, Dr Sumukh Kumble, Mr Sam Cohen, Ms Jasmine Putri, Dr Christoph Hagemeyer, Ms Hannah Pearce, Ms Edwina Jap, Dr Karen Alt,  Dr Thomas Bonnard
by Anne Crawford

A designer molecule developed by Monash University’s Australian Centre for Blood Diseases (ACBD) could prove a potent new treatment for the life-threatening blood clots that cause heart attack and stroke – without the associated side-effect of excessive bleeding.

Heart attack and stroke are leading causes of death and long-term disability in Australia, and are mostly caused by clotting (thrombosis) blocking blood to the heart or brain.

Dr Christoph Hagemeyer, group leader of the ACBD’s NanoBiotechnology Laboratory, said the new molecule had been shown in preclinical tests to be effective and safe, and may overcome limitations of current treatments.

The molecule had been previously modified to be activated by a factor causing clotting – thrombin – effectively hijacking the body’s own clotting system to initiate the destruction of the clot.

The Monash researchers reduced its size, removing material that didn’t contribute to the task at hand, then fused the molecule with antibodies that sought out and bound specifically to the blood clot.

“This provided us with the means to give a lower but still highly effective dose to the body – it only binds to the area where it should be activated,” Dr Hagemeyer said. “You can avoid a lot of the side effects by targeting the molecule to the clot,” he said.

The fusion protein, named SCE5-HtPlg, remains inactive in the bloodstream, safely circulating without degrading essential factors preventing bleeding until it becomes activated by pro-thrombotic molecules.

“Another advantage is that a lot of current clot busters are inhibited by natural factors in the blood,” Dr Hagemeyer said. “Our molecule is a designer protein that’s not naturally occurring so it escapes these inhibitory factors.”

The protein was successfully tested in preclinical models for acute blood clotting, and for lung embolism.

“We showed you could give it at a very low dose, that it’s very efficient, and we saw no side effects,” he said.

Developing a drug with a better safety profile could open the way for treatment to be administered by paramedics at the scene of a patient who’d experienced an ischaemic stroke, he said. Such patients currently need to be administered clot-busting medication, only available in certain hospitals, by specialist doctors within 4.5 hours of symptoms – it is too risky to administer the drugs from an ambulance. But the longer it takes, the greater the damage to the brain and the risk of permanent brain damage and disability.

A clot-busting treatment that could be administered quickly and efficiently but which does not bring on harmful side effects is considered the ‘holy grail’ of research in the field.
The ACBD researchers hope to work with the pharmaceutical industry to bring the molecule into clinical trials.

The research, supported by National Heart Foundation of Australia and NHMRC funding, is published in the Journal of the American Heart Association. First author is Dr Thomas Bonnard, funded by a William Harvey International Translational Research Fellowship from the European Union. The initial work was carried out at the Baker Research Institute, where the team was working previously.

The Australian Centre for Blood Diseases, in Monash University's Central Clinical School, is affiliated with The Alfred Hospital's Haematology Department.

Bonnard T, Tennant Z, Niego B, Kanojia R, Alt K, Jagdale S, Law LS, Rigby S, Medcalf RL, Peter K, Hagemeyer CE. Novel thrombolytic drug based on thrombin cleavable microplasminogen coupled to a single-chain antibody speciļ¬c for activated GPIIb/IIIa.

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