Deadly cures: a venom-inspired ASIC1a inhibitor for treating ischemic injuries of the brain
Speaker: Professor Glenn King
Group Leader
Institute for Molecular Bioscience
University of Queensland
Deadly cures: a venom-inspired ASIC1a inhibitor for treating ischemic injuries of the brain
Abstract: Stroke and myocardial infarction (MI) account for 27% of global mortality, yet there are no drugs available to prevent the ischemic injury they cause to the brain and heart. The drop in tissue pH during stroke activates acid-sensing ion channel 1a (ASIC1a), a proton-gated sodium channel, which in turn promotes programmed cell death pathways. We isolated a disulfide-rich spider-venom peptide (Hi1a) that inhibits ASIC1a with picomolar potency and exceptional selectivity [1]. Hi1a dramatically reduces infarct size and improves behavioural outcomes when administered after ischemic stroke in rats [1], improves functional recovery in rodent and pig models of MI [2,3], and radically improves donor heart recovery in rodent and pig models of heart transplantation [2,3]. Collectively, our data provide compelling evidence that ASIC1a is a novel target for drugs to reduce the burden of stroke and MI, and increase the pool of donor hearts for transplantation. With a view to clinical translation, we developed miniaturised cyclic-peptide versions of Hi1a and in 2022 founded the Brisbane-based biotech company Infensa Bioscience to advance clinical development of these ASIC1a inhibitors. Infensa has completed IND-enabling preclinical toxicology studies and GMP manufacture of their nominated drug candidate, and a Phase 1 clinical trial in healthy volunteers is nearing completion. Infensa is developing even smaller cyclic-peptides with greater ability to penetrate the blood-brain barrier for the treatment of ischemic stroke.
1. Chassagnon et al. (2017) Proceedings of the National Academy of Sciences USA 114:3750–3755
2. Redd et al. (2021) Circulation 144: 947–960
3. Redd et al. (2024) European Heart Journal 45: 1571–1574
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