Research Grant - 2021

Watch Dr Jessica Fletcher accept the research grant award and hear a bit about the project.

Multiple Sclerosis (MS) is a complex disease, involving the immune system and brain, with no clear cause and no known cure. Numerous factors, including a person’s environment, lifestyle and genetics, influence whether they will develop MS. However, many genetic risk factors identified have no clear biological role in MS. Our team has studied a family with an unusually high incidence of MS within first-degree relatives, meaning that the genetic factors outweigh the environmental and lifestyle risks that contribute to developing MS. Using this approach, we have identified a variant in a gene called NLRX1, only found in the family members with MS, and not in any of the unaffected relatives. 

We will characterize in detail the molecular and cellular consequences of the NLRX1 variant using human cells from the family members with MS, that we can transform into different kind of brain cells. These stem cell lines are produced by reprogramming blood cells from people with MS. Usually, in this approach, as we convert blood cells to stem cells and then to brain cells, we may “wipe the slate clean,” erasing the impact of the environment and lifestyle factors, and so fail to model MS. By generating stem cells from families with an unusually high incidence of MS, where the familial genetics are the primary driver of disease, we have a very real opportunity to generate the first ever in vitro model of MS that can be used to learn the cellular pathways that are responsible for disease initiation and progression. We will use this tool to identify the biological role of the NLRX1 variant in the underlying cause of MS, and the earliest contribution of brain cells to propagating MS pathology. We expect the outcomes from this study will result in the identification of a pathway that can be targeted for therapeutic intervention that will feed into our fundamental research to clinical trial pipeline (as per TAURUS clinical trial; ACTRN12619001196134).

Outcomes:

Our overall hypothesis is that dysregulated NLRX1 signalling leads to MS-associated neurodegeneration. NLRX1 is a protein expressed in all cells, and its primary known function is to ‘dampen’ inflammatory signals that occur after tissue damage or viral infections. It does this by binding to another protein (MAVS) – but we believe the MS-associated NLRX1 variant prevents it from binding effectively.

Firstly, we performed experiments to compare the normal and MS-associated variants of this protein. However, we encountered technical difficulties in determining if MAVS was binding to the normal NLRX1 variant. We will continue troubleshooting this problem and hope to reach a conclusion soon. In the second part of the project, we are examining the function of NLRX1 in the family members with MS, unrelated people with MS, and people without MS (controls).

While these research outcomes are not finalised, they are the first step into developing a new ‘humanised’ model of MS. This is very important for both our ability to design effective brain repair therapies, and for our ability to understand how MS develops and progresses. One of the key limitations of current preclinical models is that none of them faithfully recapitulate either the cause of MS or the full range of disease processes that occur in people with MS. By determining if these gene variants that are strongly associated with MS development in families have biological effects linked to neurodegeneration, we will be able to establish a novel cellular model of MS. This will be a highly significant outcome for MS brain research, generating a novel platform of therapeutic testing for new brain repair treatments.

Outcomes submitted January 2023.

Learn more about Dr Fletcher and her research in our Researcher Profile >>