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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.
The project led by Associate Professor Lachlan Rash has made notable progress in developing and testing new drug candidates targeting ASIC1 for MS. One drug candidate, Hi1a, has been shown to protect nerves in the brain and spinal cord in laboratory models of stroke and MS. In these experiments, Hi1a significantly reduced nerve damage, inflammation, demyelination, gliosis (excessive amounts of a type of cell called astrocytes in damaged areas of the brain and spinal cord), and inflammation of the brain and spinal cord.
The research team has optimised the dosing of Hi1a and found adding a type of protein called serum albumin protein increased its effectiveness. Hi1a also prevented severe disease symptoms in laboratory models. Experiments have demonstrated that Hi1a blocks cell movement ingto the brain and spinals cord, and inflammation of the brain and spinal cord, protecting against nerve damage in areas of the brain containing myelinated nerve fibres. The team is also investigating Hi1a’s effects on demyelination and remyelination using an established laboratory model known as the cuprizone model.
Additionally, the team have validated the use of ASIC antibodies for staining human brain tissues and acquired samples from the MS Brain Bank. Initial results have promisingly identified ASIC1 in MS lesions.
Collaborations with international researchers have been established, and additional PhD students have been recruited. Future work includes completing the remaining research aims, publishing findings, and further testing of ASIC inhibitors in various MS models.
These findings suggest a significant role for ASIC1a in MS and indicate that Hi1a and similar drugs could provide new therapeutic options for treating progressive MS.
Updated 31 March 2024
Dr Lachlan Rash
$323,960
2022
2 years
Current project
