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Liver flukes secrete a growth factor to heal the chronic wounding they cause while feeding in the liver of their human hosts

Parasitic liver fluke recombinant growth factor accelerates wound healing in vitro and in vivo using mouse wounding models, and offers promise in the treatment of ulcers for diabetics and the elderly

Parasite recombinant purified proteins and peptides offer great promise as an entirely new generation of therapeutics for chronic human diseases

Opportunity for partnership

The Australian Institute of Tropical Health and Medicine (AITHM) is seeking to partner with biotechnology or pharmaceutical companies to develop helminth-derived molecules as an entirely new generation of wound healing therapeutics.

The goal is to develop recombinant proteins and peptides derived from parasite secretions that promote healing of acute and chronic wounds, notably those associated with diabetes and ageing.

This will enable us to apply millennia of host- parasite co-evolution to develop biologics with good safety profiles and multiple disease targets to combat the epidemic of chronic inflammatory and metabolic diseases.

Scientific team

Alex Loukas, PhD
Professor, NHMRC Principal Research Fellow, and Director, Centre for Biodiscovery & Molecular Development of Therapeutics, AITHM, JCU, Cairns

Michael Smout, PhD
Senior Postdoctoral Fellow, Centre for Biodiscovery & Molecular Development of Therapeutics, AITHM, JCU, Cairns

Norelle Daly, PhD
Professor, ARC Future Fellow, Centre for Biodiscovery & Molecular Development of Therapeutics, AITHM, JCU, Cairns

The project

Hominids co-evolved with intestinal parasites over millennia, and only very recently in evolutionary history have we removed them from our lives in industrialised societies. The disappearance of parasitic worms has been accompanied by an explosion in the incidence of non-infectious chronic inflammatory and metabolic diseases, such as type 1 and type 2 diabetes.

Parasitic worms, such as liver flukes, graze on the epithelial surfaces of the tissues in which they reside, where by virtue of their feeding activities and their large sizes, they induce chronic wounding of the tissues. It is in the parasite’s best interests to cause minimal damage to its host, and liver flukes do this by secreting a growth factor that mops up the damage that it inevitably causes when it grazes on the bile duct walls.

Using gene silencing and recombinant protein technologies, we have shown that human liver flukes secrete a growth factor called Ov-GRN-1 that shares structural similarity to the human growth factor, granulin. Recombinant Ov-GRN-1 accelerated angiogenesis (blood vessel formation) and promoted in vitro wound healing of a human liver cell line, and produced significantly greater healing of experimentally induced tissue wounds in mice when just picomoles of Ov-GRN-1 were applied topically.

Cells exposed to Ov-GRN-1 underwent changes in protein and gene expression that support a role in accelerated wound resolution, notably overexpression of a family of chemokines.

The technology

To identify the minimal sequence required for functional activity of Ov-GRN-1 and secure the best possible intellectual property position, we synthesised a peptide derived from Ov-GRN-1 and showed that it retains functional wound healing activity in vitro and in vivo, and now plan to submit this peptide to a thorough pre-clinical evaluation as an entirely new class of wound healing agent.

Ov-GRN-1 and its derivatives offer promise for treating wounds where existing repair mechanisms are insufficient, such as diabetic foot ulcers, or chronic non-healing wounds in the elderly.

Our approach confers a number of competitive advantages over current gold standard wound-healing agents – this is a first-in-class approach, using millennia of host-parasite co-evolution to guide rational drug design and delivery.

Chronic wounds take substantial time to heal and are expensive to treat.

Advanced wound care and closure products are increasingly gaining popularity as solutions for treating chronic wounds, and are increasingly used in conjunction with traditional products such as dressings, due to their effectiveness in promoting faster healing.

Applications - market size

The global wound care market is predicted to reach $20 billion by 2020 from $15 billion in 2014. The advanced wound care and closure market for ulcer treatment (to which Ov-GRN-1 would belong) is expected to grow to over $7.8 billion by 2020 with diabetic foot ulcer management being the most prominent segment.

The factors driving the market growth include an alarming increase in the diabetic and obese population, and an ageing population. The wound care market is dominated by North America with the U.S. accounting for the major market share.

Demand for wound healing products in Asia is predicted to grow at the highest rate over the next few years because of increasing awareness of wound healing products, an ageing population, rising diabetic wounds due to changing lifestyle factors, and an increasing number of patients with pressure sores and ulcers.

Figure 1. Ov-GRN-1 stimulated wound repair in vitro. (A) Predicted structure of the Ov-GRN-1 protein showing the beta-hairpin stack held together by six disulphide bonds. (B) Rate of in vitro scratch closure of wounded H69 human cholangiocytes treated with 20 nM recombinant Ov-GRN-1, TRX control protein or media alone.

 

Figure 2. Ov-GRN-1 stimulated wound repair in vivo. (A) Sequential images over four days of healing wounds revealed the response of mice to treatment with recombinant Ov-GRN-1 or rTRX control; skin-deep wounds were made with a 5 mm diameter biopsy punch between the ears of BALB/c mice. (B) The rate
of wound healing over four days was measured; wound closure was determined electronically from photographs by measuring wound areas. (C) Assessment
of the angiogenic properties of recombinant Ov-GRN-1 in the chorioallantoic membrane (CAM) assay. The numbers of blood vessels in quail eggs that grew on 0.5 cm2 lter paper soaked in rOv-GRN-1 or vehicle (control) were ascertained after incubation for 15 hours. Data points are the averages of two experiments with 3-5 biological replicates displayed with SEM bars. *=P<0.05, **=P<0.01, ***=P<0.001, ****=P<0.0001, ns = not signi cant.