The science of ASIC1a: how Infensa Bioscience is protecting hearts and brains with a different approach to treatment

A drug candidate developed by Infensa Bioscience and inspired by a molecule found in spider venom is entering clinical trials with the potential to transform the treatment of heart attack and stroke. Infensa’s Chief Scientific Officer, Glenn King, explains the science behind this exciting development in cardiac and neurological care.

The problem: acid damage in the heart and brain

Heart attack and stroke are the two leading causes of death worldwide, and they can cause long-term disability in survivors. The long-term consequences of a heart attack can include end-stage heart failure, the only cure for which is a heart transplant – but the pool of donor hearts is much smaller than the number of recipients requiring a transplant.

Heart attack, stroke and heart transplantation all involve injury that occurs due to a lack of oxygen-rich blood flowing to the affected tissue, known as an ischaemic injury. In the case of heart attack and ischaemic stroke, this is caused by a blockage in an artery leading to the heart or brain, while in heart transplantation, it occurs when the heart is removed from the donor.

Current treatments focus on removing the blockage that reduces blood flow to the affected organ, but there are no drugs on the market today that protect the heart and brain from the tissue death caused by lack of oxygen.

Infensa is striving to change this.

The science: acid-sensing ion channels and ASIC1a

Both the heart and brain require large amounts of oxygen to power their activity. When the flow of oxygen stops, these organs switch to a different, less-efficient form of metabolism so they can continue to produce the fuel needed to function. While this keeps the organ – and the person – alive in the short-term, it also causes a build-up of lactic acid.

Glenn explains that the increase in acid activates proteins called acid-sensing ion channels.

“Ion channels are proteins usually located on the outer membranes of cells that control the influx of electrically charged ions such as sodium and calcium,” Glenn says. “As the name suggests, acid-sensing ion channels are activated by acid and hence they turn on during conditions of tissue acidosis.”

During heart attack and stroke, an acid-sensing ion channel known as ASIC1a on the outer membrane of neurons and heart muscle cells becomes activated. This causes an influx of sodium and calcium ions, which triggers intracellular metabolic pathways that cause billions of cells to die by suicide, resulting in permanent damage to the heart or brain with potentially fatal consequences.

Inhibition of ASIC1a results in significantly less tissue damage in the heart or brain – making this ion channel a novel target for life-saving treatments.

Unravelling ASIC1a’s role in heart attack, stroke and heart transplantation

Glenn said the role of ASIC1a in stroke was established by researchers working in North America.

“These researchers published a remarkable paper in 2004 showing that if you genetically knocked out the ASIC1a channel in mice there were no ill effects, but when these mice were given an ischaemic stroke, the resultant brain damage was reduced by 60%,” Glenn says.

“I immediately thought that if you could knock out ASIC1a pharmacologically, it might  be an effective neuroprotective treatment for stroke.”

He began to investigate inhibitors of ASIC1a, teaming up with University of Queensland colleague and cardiac physiologist Nathan Palpant to expand the research to heart attack.

ASIC1a’s presence in the heart was discovered by Glenn and Nathan, who is now Infensa’s Head of Biology.

“Nobody knew ASIC1a was present in the heart until we looked – we sifted through transcriptomic data and showed that ASIC1a is expressed in both rodent and human hearts.”

Nathan and Glenn then showed that ASIC1a mediates ischaemic injury of the heart by demonstrating that hearts with a genetic knockout of ASIC1a recovered much better in a model of heart attack. They then worked with Peter MacDonald, a heart transplant surgeon from the Victor Chang Cardiac Research Institute, to demonstrate that blocking this channel also improved the viability of donor hearts.

Infensa’s approach: a venom-derived ASIC1a inhibitor

Infensa’s lead drug candidate is inspired by a peptide that Glenn’s group found in venom of the K’gari funnel-web spider. This peptide – Hi1a – is the most potent and selective inhibitor of ASIC1a described to date. Hi1a has been shown to protect the brain during stroke, salvage heart function during a heart attack, and enhance the viability of donor hearts.

Infensa scientists developed a miniaturised version of Hi1a that is easier to manufacture at scale, while retaining the ability to block ASIC1a and its harmful effects.

Glenn explains why venoms, which can harm human health, are also a promising source of therapeutics.

“Venoms are complex cocktails of hundreds of compounds, the vast majority of which are not harmful to humans,” he says. “Venomous invertebrates evolved venoms that incapacitate prey primarily by targeting ion channels, and hence they are the best known source of potent and selective ion channel modulators.”

The life-saving potential of ASIC1a inhibitors

The deep insight into the pharmacology of ion channels and the underlying biology of heart attack and stroke offered by Glenn and Nathan, combined with the extensive drug discovery experience of Infensa staff including Mark Smythe, Michael Ankersen and Ming Chong, has allowed Infensa to develop a drug candidate that could be the world’s first cardio- and neuroprotective treatment.

A drug that prevents the tissue damage associated with heart attack, stroke and heart transplantation would save millions of lives and reduce the burden of disability.

The company is also exploring ASIC1a’s role in other forms of ischaemic injury.

“It’s well-known in biology that G protein-coupled receptors are the most common human drug target, but very few scientists realise that the second-most common human drug target is ion channels,” Glenn says.

Ion channels are very challenging to target with small molecules, which creates a tremendous opportunity for peptide therapeutics that target these receptors.

And for those that doubt the potential of peptide drugs, Glenn points out that, “Currently, the world’s best-selling drug, with projected sales of over USD30 billion in 2025, is a large peptide commonly known as Ozempic or Wegovy”.

Molecular structure of Hi1a, a potent and selective ASIC1a inhibitor