Therapeutic Programs

Inflammatory bowel disease (IBD) is a chronic and incurable disease characterised by episodic and disabling inflammation of the gut.  Current therapeutic strategies aim to decrease the frequency and severity of inflammatory episodes to prevent progression of bowel damage and avoid disabling disease with need for surgery.  However, these therapeutic options suffer from poor compliance, toxicity or cost.

There is an urgent need for better therapeutics.  With clear evidence that intestinal immunity is regulated through microbiome-immune crosstalk, the microbiome has now emerged as a valuable potential source for immune-modifying IBD therapeutics.

Researchers at The University of Queensland (UQ) have isolated gut bacteria that secreted soluble suppressors of the pro-inflammatory NF-κβ pathway, and identified a novel class of NF-κβ inhibitory bioactives.  Based on the bioactives, a lead compound with potent NF-κβ activity (IC₅₀ = 1 nM) was synthesised.

Preliminary pharmacokinetic profiling in mice shows that the lead compound is detectable at active concentrations throughout the ileum and colon less than 1 hour following oral administration and remains at concentrations >100×IC₅₀ for >6 hours.

Key features

• Leverage benefits of microbiome to treat IBD
• Novel molecules potently inhibit NF-κβ pathway throughout the colon
• Comparable reduction in disease severity to biologic therapies
• Orally active, with >6 hours gut stability and favourable PK profile.

The prevalence of diabetes mellitus continues to increase in both Australia and worldwide and it remains the number one cause of chronic kidney disease.  There are currently no treatments for diabetes induced kidney fibrosis and current treatments for diabetic nephropathy only slow down the disease progression, with the patients still progressing to end-stage renal disease and requiring renal replacement therapy.

University of Queensland researchers have developed a 10 amino acid ACE-2 stimulator peptide derived from snake venom useful for the treatment of kidney diseases and inflammation.  Preliminary data demonstrated that the lead peptide 2A has strong anti-inflammatory effects and prevents the expression of markers of fibrosis and inflammation in culture cells.  2A also attenuated kidney fibrosis and inflammation in diabetic mouse models and reduced blood glucose levels without any effect on body weight.

Key Features

• ACE-2 stimulator with strong anti-inflammatory effects
• Stable: peptide detected in multiple organs after 24 hours
• Safe: no observed adverse effects in diabetic mice.

Researchers at the Institute for Molecular Bioscience (IMB) at The University of Queensland (UQ) have developed a novel peptide-based inhibitor of the voltage-gated sodium channel 1.7 (Na_v1.7). Loss-of-function mutations of SCN9A, the gene encoding Na_v1.7, have been identified as the cause of congenital insensitivity to pain, a rare condition characterized by the inability to sense pain in otherwise normal individuals.  Gain-of-function mutations of SCN9A are the cause of two hereditary pain disorders, inherited erythromelalgia and paroxysmal extreme pain disorder. Both disorders are associated with redness, swelling and burning pain and thus, pharmacological inhibition of Na_v1.7 is a promising therapeutic strategy for the treatment pain.

Key features

• A peptide-based inhibitor targeting the resting state of voltage-gated sodium channel 1.7 (Na_v7)
• Potent (nanomolar activity) and selective for Na_v7 over other Na_v isoforms
• Proof of concept data in post-surgical and other rodent models of pain
• Potential for use in other indications.

Applications

Therapeutic applications of the Na_v1.7 inhibitor include:

• Post-operative pain;
• Acute pain;
• Chronic cough;
• Cancer, and
• Itch.

Novel, selective, orally active small molecule antagonists (and agonists) of the human protease-activated receptor 2 (PAR2) have been developed for the potential treatment of inflammatory diseases, metabolic syndrome and cancer.

Key Features

• Novel small molecules
• Orally active
• Effective in models of acute and chronic inflammation, IBD and obesity
• Selective and potent
• Novel target and unique mechanism of action.

Small molecule inhibitors of hematopoietic prostaglandin D2 synthase (HPGD2S) for inflammatory disease including DMD and asthma.

Key Features

• Potent, selective and orally administrable small molecule compounds
• Down-regulates multiple clinically validated targets
• Selective expression resulting in improved safety – HPGD2S is primarily expressed peripheral tissues (mast and Th2 cells)
• First in class opportunity for the treatment of asthma and allergic rhinitis

Diseases driven by chronic inflammation are major health burdens and controlling inflammation is an important preventative and therapeutic goal. A network of over 40 ‘Complement’ proteins is produced in blood and on cell surfaces in response to infection/injury. Complement protein C3 is a central mediator of all avenues of complement activation leading to pathogen destruction and elimination. However, blocking C3 also blocks beneficial roles of complement cascade in fighting infection.

University of Queensland (UQ) researchers have developed multiple series of novel, potent and selective, small organic molecules that mimic C3a (agonists) or inhibit its action (antagonists).

Key Features

• Novel small molecule modulators of C3aR
• Potent and selective for human/mouse C3aR
• Orally active in inflammatory disease models
• Distinct ‘Complement’ target and mechanism of action.

Potential applications

The C3aR antagonists have potential as treatments for inflammation-related diseases where C3aR has been implicated as important, including but not limited to:

• Asthma, allergies, respiratory diseases
• Arthritis, diseases of musculoskeletal system
• Metabolic Syndrome (including obesity, diabetes and cardiovascular disease)
• Inflammatory Bowel Disease (IBD), ulcerative colitis
• Autoimmune diseases (e.g. lupus, multiple sclerosis)
• Neurodegenerative diseases
• Cancers.