Current MS treatments act on the immune system dampening down its response. Of the 15 drugs currently available in Australia only 2 are used for the treatment of progressive MS.
This project directed by Dr Lachlan Rash at the University of Queensland addresses a major unmet need for drugs that protect the nerves in the brain and spinal cord, targeting the underlying mechanisms of progressive MS to prevent nerve degeneration.
In MS, the inflammatory process results in an increase in the acidity in the brain and spinal cord. Acid sensing proteins, such as the acid-sensing ion-channel (ASIC1) are increased in laboratory models of MS. Blocking these with a fairly non-specific chemical blocker called amiloride resulted in a reduction in relapses and nerve damage in laboratory models.
In this project, Dr Rash and his team will examine the effect of a very specific ASIC1 inhibitor, called Hi1a, in a laboratory model of progressive MS. Dr Rash has previously demonstrated that this molecule has a potential protective effect on nerves following stroke, and holds a patent for this molecule for it “neuroprotection” properties. In this project, he will test the drug, as well as versions of the drug modified for improved persistence in the body, on measures of movement in the progressive MS model, compared to amiloride. He will also assess whether nerve damage and immune system activation are reduced in response to the drugs. It is hoped that this will provide neuroprotective effects, but avoid the side effects that occur due to lack of target specificity of amiloride.
If successful, this will provide the first evidence of effectiveness for this potential new drug candidate to protect the brain and spinal cord in progressive MS. This would pave the way to bring this neuroprotective drug candidate to the clinic for progressive MS.
Dr Rash and his team have shown that Hi1a with a lipid added onto it, which improves the half-life and uptake into the central nervous system, has a protective effect when administered to laboratory models. The team administered different doses in laboratory models of MS and found that even a low dose of Hi1A provided decent protection against motor deficits, with the laboratory models developing about 30% less severe motor deficits than the untreated laboratory models. The medium doses were even more protective, resulting in about 50% reduction in motor deficits than untreated laboratory models. The high dose, however, only provided mild protection, suggesting it may have some off target effects that could potentially be a problem if given chronically in the MS clinic.
To understand how Hi1A provides protection, Dr Rash and his team studied spinal cords taken from laboratory models of MS and models without MS with either no treatment or treatment with the medium dose of Hi1A. They found that there was substantially less demyelination in laboratory models treated with Hi1A compared to those that weren’t treated. There was also less movement of cells into spinal cord lesions. These findings are consistent with the behavioural protection observed in the laboratory models.
Following this, Dr Rash and his team compared the protective effects of lipid-tagged Hi1A with diminazene, a small molecule that also blocks ASIC. Diminazene did provide protection against motor deficits but not to the extent of Hi1A. They also compared Hi1A with SBMS1a, a molecule that blocks ASIC1a discovered by the team that has better properties than Hi1A. They found that SBMS1a had slightly better protective activity than Hi1A.
Dr Rash has presented this research at several national conference and is currently preparing a manuscript for publication in a scientific journal. He is now extending this work and perform large scale lipid tagging and dosing studies on SBMS1a as part of the MS Australia Targeted Call Project Grant he was awarded.
Updated: 31 March 2022
Updated: 21 January, 2020
Laboratory research that investigates scientific theories behind the possible causes, disease progression, ways to diagnose and better treat MS.
Research that builds on fundamental scientific research to develop new therapies, medical procedures or diagnostics and advances it closer to the clinic.
Clinical research is the culmination of fundamental and translational research turning those research discoveries into treatments and interventions for people with MS.