Research Projects Focus on Novel Therapies for Multiple Sclerosis

The research projects involve:

• the study of working memory training in patients with multiple sclerosis (MS)
• testing the idea that blocking an enzyme called sulfatase will increase the ability of immature oligodendrocyte precursor cells to mature and begin to repair myelin

Janet L. Shucard, PhD, associate professor of clinical neurology, is principal investigator on the research that will build off the findings of a pilot study of working memory training in MS and controls.

In the pilot study, a working memory training program and a perceptual processing speed training program were developed, which allowed participants to complete computer-based training at home.

Its findings suggest that working memory training and process speed training produce different but significant changes in cognitive performance and brain function.

Shucard, associate director of the Division of Cognitive and Behavioral Neurosciences in the Department of Neurology, says the aim now is to evaluate the effects of two targeted training programs on cognitive function in MS, a working memory training paradigm (visual-verbal n-back task) and a perceptual processing speed paradigm (visual search task).

The effects of these two training paradigms in comparison with a group that does not train (no-contact control group) will be assessed using pre- and post-test measures of specific cognitive functions, functional dense-electrode electrophysiology, conventional and unconventional structural MRI and functional MRI (fMRI).

“This neuroscience-driven approach to working memory training in MS will allow us to examine not only the behavioral/cognitive changes associated with training, but also training-related changes in brain structure as measured by MRI, and training-related changes in brain function as measured by both fMRI and dense-electrode electrophysiology,” Shucard says.

This approach will provide information about the efficacy of working memory/processing speed training in patients with MS, as well as about neural plasticity of distributed neural networks underlying working memory.  

“The study will be the first to examine separately the effects of working memory and processing speed training in adult MS patients and it will be the only study to date to examine the effects of these training paradigms on cognitive performance and on a range of functional and structural neuroimaging measures, simultaneously,” Shucard notes.

Because working memory and processing speed are primary cognitive deficits in MS, these specific training paradigms may be particularly useful for improving cognitive functioning in MS patients.   

“The strengthening of these cognitive abilities may help to prevent or delay the impact that cognitive deficits have on quality of life, vocational status, and disease-related outcomes,” Shucard says.

The NMSS has funded the three-year study, titled “The Effects of Working Memory Training on Brain Function, Structure, and Cognition in MS,” in the amount of $609,000.

Co-principal investigators in the Jacobs School of Medicine and Biomedical Sciences are:

• Thomas J. Covey, PhD, assistant professor of neurology
• David W. Shucard, PhD, professor of neurology and director of the Division of Cognitive and Behavioral Neurosciences

Co-investigators in the Jacobs School are:

• Ralph H. Benedict, PhD, professor of neurology
• Michael G. Dwyer III, PhD, assistant professor of neurology and biomedical informatics
• Bianca Weinstock-Guttman, MD, professor of neurology
• Robert Zivadinov, MD, PhD, professor of neurology

A three-year research project titled “Targeting Extracellular Sulfatases to Accelerate Oligodendrocyte Progenitor-Based Myelin Repair and Regeneration” has been funded by the NMSS in the amount of $580,000.

Its primary goal is to determine the role of heparin sulfate proteoglycan (HSPG) sulfation and delineate sulfatase enzymes as novel and efficacious drug targets for regenerative therapy in MS, according to Fraser J. Sim, PhD, associate professor of pharmacology and toxicology and principal investigator on the grant.

The brain contains a population of neural stem/progenitor cells that remain dormant during adulthood.

These cells are commonly referred to as oligodendrocyte progenitor cells (OPCs) and give rise to specialized cells known as oligodendrocytes. Oligodendrocytes and the myelin that they produce are vital for normal neurological function.

When oligodendrocytes are lost or damaged in demyelinating diseases such as multiple sclerosis this contributes to severe and progressive disability, Sim notes.

“Importantly, OPCs can generate new oligodendrocytes, restoring lost myelin and promoting functional regeneration,” he says. “As such, OPCs represent a promising untapped source of stem/progenitors that when properly stimulated could lead to significant regeneration in MS and other diseases.”

Unfortunately, in MS the inhibitory tissue environment prevents OPC-mediated regeneration, Sim says.

“Sulfation is a biochemical modification that alters how the tissue environment signals to OPCs,” he says. “As such, it is in a unique position to alter the chemical communication of OPCs with the inhibitory MS environment.”

“We hypothesize that by blocking sulfatases we will improve both spontaneous myelin repair, but also further potentiate the ability of transplanted human cells to repair the MS brain,” Sim adds. “This is important as future transplantation therapies will need to overcome the same inhibitory environment that prevents spontaneous repair.”

Sim says the project is significant, as it will define a new role for HSPG sulfation and sulfatases in myelin repair.

“We will characterize the potential of a new drug and identify novel approaches to enhance myelin repair by stem/progenitor cells,” he says.

“Furthermore, we anticipate that modification of human OPC sulfation will make cells resistant to the otherwise inhibitory environment and thereby significantly increase the likelihood of success for future stem cell-based transplantation therapy in demyelinating disease.”

M. Laura Feltri, MD, professor of biochemistry and neurology, is a co-investigator from the Jacobs School.

Other co-investigators are: Steve Fancy, PhD, and Joanna Phillips, MD, PhD, both of University of California, San Fransciso.