Liver fluke key to chronic wound treatment

James Cook University

Thursday, 08 November, 2018

Liver fluke key to chronic wound treatment

James Cook University (JCU) researchers have developed a promising new treatment for chronic wounds, utilising a protein isolated from a surprising source — a parasitic Thai liver fluke, Opisthorchis viverrini.

As explained by JCU parasitologist Dr Michael Smout, chronic or non-healing wounds, which particularly afflict diabetics, smokers and the elderly, are wounds for which few drugs effectively promote healing and closure. A growth factor-based treatment, Regranex, is approved for use in the United States and South Korea but is effective in only 50% of cases and has not been able to solve the high recurrence rate.

“Every day 12 Australian diabetics have a limb amputated because of a chronic wound,” Dr Smout said. “Globally, it’s one every 30 seconds.”

A Research Fellow at JCU’s Australian Institute of Tropical Health and Medicine (AITHM), Dr Smout and his colleagues investigate ways to exploit the therapeutic properties of tropical organisms — including parasites. He revealed, “As part of our work on a potential vaccine to protect people from the Thai liver fluke, we established that the granulin molecule it produces has a hidden talent — it supercharges healing.

“That was a promising start, but we soon hit a major roadblock. We found that granulin didn’t cooperate well with recombinant DNA techniques, so we were unable to reproduce it in the quantities we needed for larger-scale testing.”

The solution was to build their own peptide — and while their first version demonstrated potent wound healing in mice and achieved good results with lab-grown human cells, the latest model shows even greater promise. In research published last year, an AITHM team outlined its success in identifying and reproducing the active parts of a molecule of granulin produced by the Thai liver fluke.

“In biology the structure and fold of a molecule can be critical to its function and stability, and NMR (nuclear magnetic resonance) spectroscopy revealed that this molecule is quite complex in terms of its structure,” said Professor Norelle Daly, whose research explores the potential of peptides as drug candidates.

PhD candidate Mohadeseh Dastpeyman worked with Professor Daly and her team to rebuild the molecule, piece by piece. Dastpeyman explained, “We identified those elements of the granulin molecule that are critical to healing, and incorporated them in a synthetic peptide that will be reliably stable.”

The rebuilt peptide, currently known as P4A, has demonstrated double the healing power of the first synthetic version, with Dr Smout saying, “In our tests P4A improved wound healing by 43% in mice. This is extremely promising if you consider that Regranex achieves a 22% improvement in healing.

“We already know, from work published earlier this year, that P4A stimulates blood vessel formation — another important part of wound repair.

“These are extremely encouraging milestones in our search for a powerful weapon against non-healing wounds.”

The patent application for P4A was published in March of this year, while the latest research was published in the Journal of Medicinal Chemistry in September. The next phase of the project, according to Dr Smout, is to secure funding partners to help the research progress from lab-based success to clinical trials, ultimately giving hope to patients who face the prospect of losing limbs because of non-healing wounds.

“We’re confident we have a very strong contender for what could one day be a cream that a diabetic could apply at home, avoiding a long and costly hospital stay and possible amputation,” he said.

“A distinguishing feature of our peptide is that it’s informed by the millennia in which humans and liver fluke have evolved together, and so far that’s proving to be a significant advantage.”

Image caption: Dr Michael Smout in the lab.

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