Inflammation and death of the oligodendrocyte cells that form the insulating sheath of myelin around nerve fibres (axons) contribute to the pathology and symptoms of MS early in the disease course. Later in the disease, a progressive failure of myelin repair and subsequent degeneration of axons leads to persistent neurological disability. There are currently no drugs that can replace or repair damaged myelin or oligodendrocytes.
The failure of normal myelin repair also represents a barrier to the potential use of transplanted stem cells for the treatment of MS. In this project, Professor Brew will investigate a method to enhance the natural repair mechanisms in the brain and also optimise the reparative potential of transplanted stem cells.
Inflammation in the MS brain appears to disturb the normal processing of the essential amino acid tryptophan, which is involved in many repair mechanisms, including remyelination. Tryptophan is normally processed through the ‘kynurenine pathway’, and produces potentially toxic chemicals including quinolinic acid and kynurenic acid. Disruptions to tryptophan processing may be playing a role in the failure of myelin repair in MS. Professor Brew aims to see if restoring the kynurenine pathway myelin-producing cells will restore their capacity for repair in the MS brain.
The findings of this project will have significant implications for the development of new therapeutic approaches for MS and in particular, will advance progress towards the therapeutic use of stem cells in the treatment of multiple sclerosis.
This project had a number of separate aims each forming a piece of the puzzle to understand the full effects of the kynurenine pathway and its relevance to MS.
Firstly, Professor Brew’s project aimed to show that myelin-producing oligodendrocyte cells express the full kynurenine pathway and produce quinolinic acid and kynurenic acid. The team have been able to demonstrate this in several different types of nerve stem cells from both mice and humans, including myelin-producing cell precursors, and in mice with MS-like disease. They showed that one of the pathway products (kynurenic acid) is favoured over the other (quinolinic acid).
Professor Brew also aimed to assess the effect of modulating the kynurenine pathway on the growth and development of these cells, and showed that by activating the kynurenine pathway, these cells were preventing from developing into functioning myelin-producing cells (oligodendrocytes). This finding means that deliberately inhibiting the kynurenine pathway could improve the growth and development of nerve cells in people with MS.
The final aim was to investigate the effects of interferon beta, a common MS medication, on the function of these stem cells. Laboratory experimentation has shown that the interferon-beta may inhibit the repair potential of stem cells and that this may involve the kynurenine pathway. Professor Brew has investigated this and shown that interferon beta can inhibit the growth and reproduction of these cells.
These experiments are a crucial first step in the pathway towards the development of a new medication for MS. This potential new approach to treating MS will require extensive testing and refinement in animals with MS-like disease, followed by careful progress towards clinical trials in humans.
This promising work will have implications for the use of stem cell therapies in MS. Two manuscripts have recently been published in scientific journals, with new and upcoming results currently in preparation for publication.
Three additional manuscripts are currently in preparation.
Updated: 31 March 2013
Updated: 06 January, 2012