Multiple Sclerosis (MS) is a widespread disease that can cause severe physical and mental disability. Relapses in MS are typically characterized by development of new lesions in white matter of the brain including the spinal cord. This includes varying degree of inflammation, destruction of myelin (a fatty sheath that surrounds the axis of nerve cells) and ultimate damage to the axis or axons of neural cells. Though mechanisms are not well-understood, histological and magnetic resonance imaging (MRI) studies have revealed that remyelination (i.e., repair of the myelin sheath) can occur spontaneously in some lesions by endogeneous progenitor cells (i.e., stem cells that are naturally present in the brain) evolving into myelin producing cells known as oligodendrocytes. It has been suggested that transplanted stem cells evolving into oligodendrocytes could facilitate the remyelination process and hence help patients in their recovery. Indeed studies in animals have shown that certain stem cells are able to achieve remyelination. However, there are currently no non-invasive tools to tell which specific brain pathways are damaged or likely to be damaged by demyelination, to quantify the damage, or to assess the degree of remyelination and repair of axons following a specific therapy inside a living person. This proposal will apply recent MRI techniques such as Diffusion Tensor Imaging (DTI) and DTI-tractography to develop a tool that will be able to quantify non-invasively the degree of demyelination and axonal damage prior to therapy, and then quantify the remyelination and axonal repair achieved by transplanted stem cells intended to facilitate the remyelination process. The proposed two-year phase will focus on developmental studies using a rat MS model but the tool developed will be translatable to humans.
Statement of Benefit to California:
Multiple Sclerosis (MS) is a significant health problem in California with a multitude of clinical trials underway to test new drugs and treatment strategies. Persistent myelin damage is a hallmark of MS. The risk is that demyelination over time may damage certain axons, leading to impairment of specific cognitive function. Though the mechanisms are not well-understood, it is known that spontaneous remyelination, attributed to endogeneous progenitor cells, occurs in some cases but also fails in others. It has been suggested that transplanted stem cells evolving into oligodendrocytes would facilitate the remyelination process and thus transplanted stem-cell therapy represents a treatment for MS with great potential and hope for the future. California is one of the few states in the US where such treatments could be designed and tested in humans and thus stands to benefit from strategies and tools designed to facilitate the development of stem cell therapy in MS.
Currently there are no non-invasive tools to quantify the damage to axons by demyelination or to assess the degree of remyelination and repair of axons in-vivo following stem cell therapy. This proposal will apply recently developed MRI techniques such as Diffusion Tensor Imaging (DTI) and DTI-tractography to develop a tool that will be able to detect the location of demyelinated regions non-invasively and in-vivo. It will also be able to quantify the degree of demyelination, identify specific brain pathways and axonal tracts affected by the lesions, and quantify damage to these pathways before and after stem-cell treatment. The proposed two-year phase will focus on developmental studies using a rat MS model but the tool developed will be translatable to humans. Thus the proposed development of the DTI tool should be of great use to the State of California as it spearheads the move toward monitoring the viability and efficacy of stem-cell therapy in MS.