Mitochondrial Dysfunction and Disease Progression

While the last several years have seen great strides in the treatment of relapsing forms of multiple sclerosis (MS), progressive MS, responsible for the majority of MS-related disability, lags far behind. Despite much research, the lack of understanding related to what causes patients' relentless decline in function results in an inability to develop targeted treatment strategies suitable for clinical trials. This grant has two main goals. The first goal is to extend our preliminary study on rat neurons treated with the cerebrospinal fluid (CSF) of MS patients to a larger number of progressive patients in order to validate our initial findings and extend the study to include analysis of human neurons. The initiating Principal Investigator (PI) (Dr. Casaccia) and the Partnering PI and Clinical Neurologist (Dr. Katz Sand) have recently identified components that are present in the CSF of progressive patients that impair the ability of rat neurons to produce energy. The partnering PI, Dr. Quinzii (Columbia University), together with her collaborator Dr. Fossati (at NY Stem Cells), has characterized human neurons generated from stem cells derived from skin biopsies of progressive patients and detected the presence of energetic deficits. The experimental plan will build on these results and test hypotheses of disease progression. The overall goal is to improve our understanding on how to stop neurons from degenerating and stop clinical progression. The second goal is to ask whether it is possible to define a progressive disease course on the basis of combined biochemical, functional and imaging measurements. The initiating PI will be responsible for the biochemical assessment of CSF and serum samples and, together with partnering PI Quinzi, will also provide functional bioassays measurements of mitochondrial bioenergetics impairment in patients. These data will be combined with clinical assessment and MRI (magnetic resonance imaging) evaluations conducted by the partnering PI Katz Sand and collaborator Inglese. A 2-year clinical and imaging follow-up from the initial recruitment will allow the investigators to define whether the combined measurements can be used by clinical neurologists to define the disease course and better identify therapeutic options for patients. We expect that the completion of the stated aims of research will allow an advancement of the current knowledge of the progressive form of MS and lead to potential new therapeutic targets.