There has been great progress in drug development for relapsing multiple sclerosis (MS) in recent years. However, the development of 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. 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 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 been shown to have potent protective effects on the nerves in laboratory models of stroke. The team have 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 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.
Through a series of experiments, the team determined the best dose of Hi1a to use for protecting the nerves in one of the laboratory models of MS. In established disease, this dose significantly reduced disease severity. When administered before the onset of disease, Hi1a was able to completely prevent disease development.
Under the microscope, Hi1a was shown to reduce myelin loss, damage to nerve fibres and inflammation.
A newly developed version of Hi1a, called SBMS-1, was even more effective in protecting the nerves in pilot testing in the model, and full dosing studies of this exciting new candidate are planned. Both Hi1a and SBMS-1, which are peptide drugs, were far more potent than a small molecule ASIC inhibitor drug (called diminazene aceturate). The next stage of the project will examine the effects of Hi1a and SBMS-1 in a second laboratory model of MS.
Hi1a appears to work, in part, by reducing the entry of immune cells into the brain and spinal cord. To understand the mechanism of action of the drug, the team has found that ASICs are present on human monocytes. Monocytes are immune cells in the blood that are known to contribute to damage of the brain and spinal cord in MS. Testing is currently underway to determine whether levels of ASICs are higher on monocytes in the blood from people with MS. Future work will also examine the levels of ASICs in the brain in MS.
This work has leveraged additional funding from the US National MS Society (NMSS; April 2023- Jun 2026) to further the project.
Updated 31 Mar 2023
Updated: 14 February, 2022