Australian molecular biologists led by researchers at Centenary have made a synthetic compound that appears to allow them to control the leakiness of blood vessels. The work could lead to effective new drug treatments for strokes and tumours. Spinoffs may include an ability to reduce the side-effects of chemotherapy and inflammation.
Their lead drug candidate, known as CD5-2, was developed with the assistance of Mirrx Therapeutics, a privately owned Danish biotechnology company. Today Centenary has signed an agreement to develop this and other potential drugs with Mirrx. The agreement was facilitated by Bio-Link Australia Pty Ltd.
“Control of blood vessel permeability is extremely important for our health,” says Professor Jennifer Gamble of Centenary’s Vascular Biology research group, who heads the research team. “Within five years, we are hoping to develop drugs which can specifically inhibit the leakiness of blood vessels, a feature that contributes to the pathology of many diseases.”
“Leaky blood vessels, as manifest by tissue swelling that can ultimately obstruct blood supply, is a very important clinical problem from the emergency room all the way to rehabilitation. The potential of a useful drug preventing vascular leak is very exciting and we look forward to its clinical development in collaboration with Mirrx,” says Professor Mathew Vadas, Executive Director of the Centenary Institute.
Professor Gamble’s latest study, recently published in the important American journal Blood, looked at how microRNAs—short strings of genetic material which can control the levels of individual proteins in cells—regulate the cells comprising blood vessel walls.
In a proof of concept, the researchers made a synthetic compound that blocks the interaction of a particular microRNA with one specific protein in these cells. They found it allowed them to control blood vessel leakiness. “We have now embarked on projects to test our compound in animal models, for example, in models of liver transplants, stroke and tumour growth,” Professor Gamble says. “If it works, we can move it reasonably quickly into clinical trials, because it’s already in drug form.”
The research group initially investigated the role of the microRNA miR-27a in controlling the production of a protein that orchestrates tight junctions between the cells lining blood vessel walls. The tightness of these junctions determines the leakiness of blood vessels.
The researchers found that the higher the level of miR-27a, the leakier the blood vessel, because the microRNA interfered with the production of the critical tightening protein. But miR-27a is also involved in regulating many other different molecular interactions in cells. This means that simply knocking out miR-27a could have multiple consequences, and unwanted side-effects.
Using new technology developed with Mirrx Therapeutics A/S, the researchers fashioned a synthetic compound, called a Blockmir, which specifically disrupts the miR-27a interaction with the tightening protein and no other. So, this Blockmir provides them with the opportunity to regulate the leakiness of blood vessels without affecting anything else.
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This research is part of an important body of work underway at Centenary and around the world because the decreased ability of controlling vessel leakiness is one of the signs of blood vessels beginning to wear out or age.
In March 2014, the Centenary Institute is hosting a multidisciplinary conference on the role of inflammation in disease and ageing. The Future of Experimental Medicine Conference – Inflammation in Disease and Ageing is being organised by Professor Gamble and her colleague Professor Wolfgang Weninger.
Find out more about the conference at http://femc.mtci.com.au/