In this study, Dr Edwin Lim, is looking at a different therapeutic target to break the vicious cycle of inflammation, cell damage, more inflammation and rapid progression that can occur in MS.
Inflammation is a critical progression factor in MS. The kynurenine pathway is known to be a key regulator of the human immune response and thus likely to play a role in both the inflammatory and autoimmune mechanisms involved in MS.
This has been a three year project during which Dr Lim aimed to identify the various components of the kynurenine pathway involved in the pathogenesis of MS. The results from this innovative project are likely to lead to new diagnostic or therapeutic targets for MS.
Tryptophan is a naturally occurring amino acid that is used by the body as one of the building blocks of protein. The pathway that breaks down tryptophan, the kynurenine pathway, is important in regulating the immune response, which may be important in MS. The activation of this pathway also leads to the production of several active metabolites that may be toxic to the brain, especially to the cells that produce myelin – the support cells around neurons that are affected in MS.
Dr Lim’s results suggest that the kynurenine pathway is dysregulated in people with MS as well as in animal models of MS. He has shown that one particular neurotoxin associated with the pathway is increased in people with MS, and is showing promise as a potential biomarker to identify progression through the different stages of MS. Biomarkers are particularly useful, for example, in clinical trials to quickly show whether new therapies are working to halt the disease. Additional complex statistical analyses are underway to determine whether activity of the kynurenine pathway may be used to discriminate different subtypes of MS.
To explore the effects of alterations to the kynurenine pathway, Dr Lim first manipulated immune cells in the laboratory, and demonstrated that inhibiting this pathway lead to reductions in the toxic effects to nerve cells, and less damage to myelin-producing cells grown in the laboratory. Then, Dr Lim showed that manipulating the kynurenine pathway in a mouse model of MS, was also able to limit the production of the toxic metabolites of the kynurenine pathway in the brain and alleviate the progression of the disease in an animal model. This work indicates that altering kynurenine metabolism may be an important therapeutic approach for MS.
Work currently underway will examine the specific effect of these molecules on myelin-producing brain support cells in animal models. Dr Lim is completing the testing phase of the required techniques on cells grown in the laboratory and will now proceed to testing the effects in laboratory models of MS. This work should determine the underlying mechanism of the kynurenine pathway dysregulation in MS with results expected by the end of 2014.
Lim CK, Bilgin A, Lovejoy DB, Tan V, Bustamante S, Taylor BV, Bessede A, Brew BJ, Guillemin GJ. Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression. Sci Rep. 2017 Feb 3;7:41473. doi: 10.1038/srep41473. PMID:28155867 Free PMC Article
With another three manuscripts currently in preparation
Updated: 30 June 2014
Updated: 05 January, 2011