Deadly cures: a neuroprotective and cardioprotective drug candidate from the venom of the Australian funnel-web spider

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 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 directly activating programmed cell death pathways. We recently 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. In addition, we observed dramatic therapeutic benefit in rodent models of heart transplantation, where Hi1a radically improved donor heart recovery2.
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. However, Hi1a is a complex 76-residue peptide with six disulfide bonds, which presents a serious manufacturing challenge. I will discuss the development of smaller, less complex peptides that are easy to manufacture and may have better brain-penetration for stroke applications.
1. Chassagnon et al. (2017) Proc Natl Acad Sci USA 114: 3750
2. Redd et al. (2021) Circulation 144: 947

Brief Biography
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 bee-safe, eco-friendly bioinsecticides. Glenn’s current research focuses on the development of therapeutics to treat cardiac 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 2012–2020. Glenn has published 3 books, 19 book chapters, and more than 300 peer-reviewed journal articles.