Looking for Insights to A Rare Genetic Neurologic Disease

Amanda Furness, PhD

Amanda Furness, PhD, is a postdoctoral research fellow in the Center for Genomic Medicine at Massachusetts General Hospital. Her poster, Therapeutic insight into Mucolipidosis IV via in vitro glia models, recently won an award at Mass General’s Research Fellow Poster Celebration.

We asked Dr. Furness about her research:

What problem(s) are you addressing with this research?

Our lab is studying Mucolipidosis IV (MLIV), a genetic neurologic disease that affects children. Affected individuals have intellectual disability, limited or absent speech, difficulty chewing and swallowing, weak muscle tone that gradually turns into abnormal muscle stiffness, and problems controlling hand movements. Most are unable to walk independently.

Patients typically remain stable into their 20s and 30s when they start to develop corneal clouding, leading to blindness. Although MLIV is a pan-ethnic disease, the vast majority of MLIV patients are of Ashkenazi Jewish decent.

To date, there is neither a specific treatment for MLIV, nor a complete mechanistic model explaining its pathology. Our goal is to investigate, understand, and control the pathways affected by the disease and ameliorate the resulting clinical manifestations of MLIV.

What methods did you use?

Previous members of the lab have developed and characterized the MLIV mouse model, which is an excellent model of the disease. We have used this model to study various aspects of the disease ranging from cellular signatures to motor function.

Our prior research has shown that neuroinflammation caused by dysfunction of cells in the central nervous system — called glial cells — is an early and important sign of MLIV.

Thus, in our recently presented and published research, we developed in vitro models for two subtypes of glial cells, astrocytes and microglia, that model the dysfunction of these cells in individuals with MLIV.

The cultured cells from MLIV mice were investigated using an assay to monitor changes in proinflammatory molecule production.  The cells were also imaged using a microscope to look at structure, markers of inflammation, and the contents of lysosomes — enzyme-containing organelles that break down a variety of biomolecules.

What results did you find and how do your results expand our understanding of this topic?

The in vitro models we developed provide both a phenotypical representation of the disease, as well as mechanistic insight into the glial function in MLIV.

In attempts to find strategies to slow the progression of MLIV, we also tested fingolimod, an FDA approved drug for multiple sclerosis, on our MLIV cells. Our data show that this drug reduces pro-inflammatory signaling in cultured astrocytes from MLIV mice. Furthermore, fingolimod was also able to correct lysosomal impairment, which is a primary consequence of the disease.

What are the implications for clinical care?

Because we saw cell function recovery and proinflammatory reduction in our cell models, we can now move to a pre-clinical trial where we will determine if fingolimod can recover motor and muscle function in our MLIV mice. Success in this trial will hopefully pave the way for a clinical trial in MLIV patients.  We are currently using the glia models to screen additional drugs for other pre-clinical trials.    Our ultimate goal is to discover several compounds which could be given to MLIV patients to attack the disease and recover function from several angles.


Check out a recently published article highlighting this research!

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