Invité direction: Glenn King, Univ. of Queensland, Australia – “Deadly cures: a peptide-drug candidate for use in stroke and heart attack from venom of the lethal Australian funnel-web spider” – Reporté.

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 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 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 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