Invité Direction: Glenn King, Université du Queensland, Australie – “Deadly cures: a peptide-drug candidate for use in stroke and heart attack from venom of the lethal Australian funnel-web spider”

Résumé

Cardiovascular disease is the leading cause of death, with myocardial infarction (MI) and stroke alone accounting for 27% of global mortality. In spite of this massive disease burden, there are no drugs available to protect the heart and brain from the tissue injury caused by MI and stroke, respectively.

The reduced supply of oxygen to the heart and brain during MI and stroke, respectively, induces a switch to fuel production via anaerobic glycolysis, which leads to lactic acidosis. The resultant drop in tissue pH activates acid-sensing ion channel 1a (ASIC1a), a proton-gated sodium channel. Activation of ASIC1a promotes cell death by exacerbating intracellular calcium overload and activating programmed cell death pathways. We isolated a disulfide-rich spider-venom peptide (Hi1a) that inhibits ASIC1a with picomolar potency and exceptional selectivity. Hi1a dramatically reduces infarct size and improves behavioural outcomes even when administered up to 8 hours after ischemic stroke in rats1. More recently, we demonstrated that genetic ablation of ASIC1a leads to improved functional recovery in an in vivo mouse model of MI, and that this effect can be recapitulated by therapeutic blockade of ASIC1a using Hi1a2,3. In addition, we observed dramatic therapeutic benefit in rodent2 and pig models of heart transplantation, where Hi1a radically improved donor heart recovery.

Collectively, our data provide compelling evidence that ASIC1a is a novel target for neuroprotective and cardioprotective drugs to reduce the burden of MI and stroke, and that Hi1a is an exciting lead compound for these indications. In 2022, Infensa Bioscience was founded to commercialise this technology, with an initial focus on ST-segment elevation myocardial infarction (STEMI), the most serious form of heart attack.

1. Chassagnon et al. (2017) Proc Natl Acad Sci USA 114: 3750

2. Redd et al. (2021) Circulation 144: 947

3. Redd et al. (2024) European Heart Journal 45: 1571

Biosketch

Glenn did his PhD at the University of Sydney before postdoctoral studies at the University of Oxford. After academic stints at the University of Sydney and the University of Connecticut Health Center (USA), he joined the Institute for Molecular Bioscience at the University of Queensland in 2007. Glenn is a leader in the field of venoms-based drug and insecticide discovery. His early work on venoms led him to found Vestaron Corporation, an agricultural biotechnology company that has successfully developed eco-friendly bioinsecticides. Glenn’s current research focuses on the development of peptide drugs to treat cardiovascular and nervous system disorders. He recently co-founded Infensa Bioscience, a biotech company that aims to develop venom-derived drugs for treating stroke and myocardial infarction, and he currently serves as the company’s Chief Scientific Officer. Glenn’s laboratory maintains one of the largest venom collections in the world, sourced from more than 500 species of invertebrates including ants, assassin bugs, caterpillars, centipedes, scorpions, spiders, and wasps. Glenn is former President of the Australian Society for Biophysics, former Chair of the Australian and New Zealand Society for Magnetic Resonance, and he served on the Executive Council of the International Society on Toxinology from 2012 to 2020. Glenn has received lifetime achievement awards from the Australian Society for Biophysics and the Australian and New Zealand Society for Magnetic Resonance, and in 2023 he was awarded the Prime Minister's Prize for Innovation. He was elected a Fellow of the Australian Academy of Science in 2024. 

1. Sydney funnel-web spider

2. Blue Mountains funnel-web spider

3. K’gari funnel-web spider