There has been great progress in drug development for relapsing MS in recent years. However, developing therapies for the progressive phase of MS,  characterised by a continual accumulation of disability, has lagged significantly. There are currently no approved drugs that treat the nerve degeneration that is associated with progressive disease.
In MS, injury to the brain and spinal cord, characterised by MS lesions, is frequently associated with acid production in the nervous system. The acid-sensing ion channel 1 (ASIC1) is a protein found on nerves and on cells associated with brain inflammation in MS. The role of ASIC1 is to detect and respond to acid production in the brain that is associated with tissue damage.
The activation of ASIC1s on inflammatory cells can enhance their capacity to damage tissue. Over-activation of ASIC1 in nerves in the brain or spinal cord, as happens during brain inflammation in active MS, contributes strongly to nerve cell death. Nerve cell death is a main cause of increasing disability in MS.
Associate Professor Lachlan Rash’s laboratory has developed several new drug candidates that strongly bind to and block the action of ASIC1. One of these drug leads, called Hi1a, has potent protective effects on the nerves in laboratory models of stroke. The team has recently shown it also provides protection of the brain in laboratory models MS.
The overall goal of this project is to determine how blocking ASIC1a (a type of ASIC1) with these new drugs reduces nerve damage. The team will also investigate whether it can promote repair of the myelin sheath that insulates the nerves in the brain and spinal cord, and is damaged in MS. To achieve this, they will test Hi1a and improved versions of the drug in two laboratory models of MS.
In addition, Associate Professor Rash will investigate whether ASIC1a is found at higher levels in regions of nerve damage in MS, using samples from the MS Brain Bank. The team have also produced a Hi1a molecule with a fluorescent tag which they will explore as a new imaging marker for nerve damage in a laboratory model of MS.
Associate Professor Lachlan Rash and his team have made significant progress in developing new drug candidates targeting ASICs.
The team’s lead compound, Hi1a, has shown strong protective effects in two laboratory models of MS. In the experimental autoimmune encephalomyelitis (EAE) model, Hi1a significantly reduced nerve and myelin damage, gliosis (scarring), and inflammation, even when administered after symptoms had begun. In the cuprizone model, which is used to study demyelination and remyelination, experiments have been completed, and results are currently being analysed. The team also optimised dosing, finding that the addition of serum albumin further improved the compound’s effectiveness.
Using tissue from the MS Australia Brain Bank, the team confirmed the presence of ASICs in MS lesions and validated new methods for detecting them in human brain tissue. They also discovered that ASIC levels decrease in the peripheral blood immune cells (within the blood that circulates through the body) of people with MS. This is a novel finding, and early results suggest it may be associated with disease severity. The team is now working to understand how this change relates to symptoms and disease progression, with further validation underway.
This research contributes to the growing body of evidence that ASICs play a meaningful role in MS and highlights them as important and promising targets for future therapies. The project has also supported the development of emerging researchers, with a PhD student set to submit their thesis of this work by 30 June 2025.
These findings lay a strong foundation for future studies and the continued development of ASIC-blocking drugs for progressive MS.
Updated 31 March 2025
Dr Lachlan Rash
$323,960
2022
2 years
Current project
