There has been great progress in drug development for relapsing multiple sclerosis (MS) in recent years. However, for the progressive phase of MS, which is characterised by a continual accumulation of disability, development of therapies has lagged significantly. There are currently no approved drugs that treat the nerve degeneration that is associated with progressive disease.
Injury to the brain and spinal cord in MS, 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.
Dr Rash’s laboratory has developed several new drug candidates that strongly bind to and block the action of ASIC1. One of these drug leads, 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 of 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 do this they will test Hi1a and improved versions of the drug in a laboratory model of MS.
Dr Rash will also investigate whether ASIC1a is found at higher levels in regions of nerve damage in MS, using clinical samples from MS patients. 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.
Updated: 14 February, 2022