Parasitic hookworms have co-evolved with humans to cause chronic infections with minimal pathology
Hookworms have developed entirely novel molecular means to suppress inflammation, and experimental human infection confers therapeutic benefit against inflammatory diseases
Hookworm recombinant purified proteins protect against a range of autoimmune and allergic diseases in animal models
Opportunity for partnership
The Australian Institute of Tropical Health and Medicine (AITHM) is seeking to partner with biotechnology or pharmaceutical companies to discover and develop hookworm-derived small molecules as an entirely new generation of anti-inflammatory therapeutics.
The goal is to develop small molecules derived from hookworm secretions that suppress inflammation by promoting regulatory responses, notably the expansion and mucosal homing of regulatory T cells.
This will enable us to apply millennia of host-parasite coevolution to develop biologics and small molecules with good safety profiles and multiple disease targets to combat the epidemic of chronic inflammatory diseases.
Alex Loukas, PhD
Professor and Director, Centre for Biodiscovery & Molecular Development of Therapeutics, AITHM, JCU, Cairns
Catherine Shepherd, BSc Hons PhD candidate
Molecular Development of Therapeutics, AITHM, JCU, Cairns
Paul Giacomin, PhD
Senior Postdoctoral Fellow, Centre for Biodiscovery & Molecular Development of Therapeutics, AITHM, JCU, Cairns
Phurpa Wangchuk, PhD
NHMRC Early Career Postdoctoral Fellow, Centre for Biodiscovery & Molecular Development of Therapeutics, AITHM, JCU, Cairns
John Croese, MD
Consultant Clinical Gastroenterologist, Prince Charles Hospital, Brisbane & AITHM, JCU
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 diseases such as inflammatory bowel diseases (IBD), diabetes and allergies.
We, and others, have shown that experimental infection of people with hookworm parasites is safe and confers potential therapeutic bene t to people with IBD and celiac disease (dietary gluten intolerance).
The notion of infecting people with parasitic worms to treat inflammation is fraught with hurdles, so we sought to prove that parasitic hookworms prevent inflammation via the active secretion of proteins and small molecules into the gut tissue.
We have already identified individual molecules that confer protection against inflammatory diseases in animal models, and are working towards developing pre-clinical portfolios to accelerate these discoveries towards clinical trials.
Our technology relies on the isolation of secreted proteins, peptides and small molecules from hookworm excretory/secretory products with anti-inflammatory properties identified through a combination of in vitro, ex vivo and in vivo assays and animal models of disease.
We have characterised the hookworm secreted metabolome, and shown that selected fractions containing these small molecules protect mice against chemically-induced colitis.
Using mass spectrometry, nuclear magnetic resonance spectroscopy and medicinal chemistry approaches, we aim to isolate and structurally characterise the anti-inflammatory small molecules from hookworms and generate synthetic versions to undergo thorough assessment of efficacy in the target disease.
Our approach confers a number of competitive advantages over current gold standard anti-inflammatory therapeutics – this is a first-in-class, potentially disease-modifying approach with differentiated mechanism of action by specifically targeting regulatory immune responses.
We expect efficacy against multiple indications with potential prolonged benefit from short term therapy by resetting the effector: regulatory cell balance.
Applications - market size
The market for inflammatory disease therapeutics is enormous, and growing at an unprecedented
rate. Potential returns are high in light of clinical options and potential risks. Obvious disease target areas where current standard of treatment is insufficient include the autoimmune diseases such as IBD, rheumatoid arthritis, transplant diseases, psoriasis, multiple sclerosis and celiac disease, and allergic inflammation such as asthma, food allergies and allergic dermatitis.
Figure 1. Administration of a chloroform-methanol (C/M) extract of hookworm low molecular weight excretory/ secretory products collected in substrate A (LES-A) protects mice against weight loss caused by chemical colitis (left panel). Substrate A alone does not protect. Cells from gut tissue of mice treated with LES-A (pink bars) and cultured ex vivo secreted significantly reduced quantities of the inflammatory cytokines, IFN-γ, TNF-α and the Th2 cytokine associated with human ulcerative colitis, IL-13
Figure 2. The small mol- ecule secretome of adult hookworms. LES com- pounds (non-derivatised) were identified by GC-MS and labelled based on their reported activity (if any) in the published literature. Bubble size reflects the relative quantity of each compound. A substantial number of small molecules are of unknown function and might be hook- worm-specific. Ongoing work is focused on characterising the derivatised small molecule secretome and using RP-HPLC to identify the bioactive compounds.