One of the most vexing problems in MS is to understand why some patients get worse or progress. Put another way, a frustrated patient will frequently ask “why do all the FDA treatments work only for relapsing-remitting disease and not for primary progressive (PPMS) or secondary progressive (SPMS) forms of MS?” In the past year we have continued our work to better understand the mechanisms of disease worsening using three distinct approaches and have added a fourth new avenue of exploration as follows:
1) Direct investigation of cells form inflammatory lesions in the brain or spinal cord in inflammatory CNS diseases is hardly possible in humans, mostly because MS lesions are rarely biopsied. However, cells in the cerebrospinal fluid (CSF) likely have interacted with or have derived from inflammatory CNS lesions. Therefore, CSF cells may reflect on disease activity in the CNS and are for that reason of high interest. Considering CSF cells to be a surrogate for the target organ itself in CNS disorders, Dr. Mueller and its associates are addressing the gene expression profile of CSF cells associated with MS. MSRCNY’s unique set up and close proximity the IMSMP has allowed us to obtain and preserve all the RNA present in cerebrospinal fluid (CSF) in a patient prior to its degradation (a period of approximately 15 minutes). The RNA or CSF “transcriptome” containing thousands of transcripts is analyzed to identify those that are either unique or altered in expression in progressive MS. In work done over the past year, Mueller and his team of scientists are able to reliably differentiate between MS and control samples validating their approach. In addition, they have identified a transcript that codes for hepatocyte growth factor (HGF) that is reduced in active MS. We are currently investigating whether down-regulation of this protein is associated with progression and whether lower levels of HGF prevent optimal myelin repair.
2) Dr. Cristofanilli and his group are trying to determine if an experimental model can be created that allows for pathological analysis of the disease mechanisms pertaining to progressive tissue. They have already established in cell experiments and in mice that specific cellular products derived from PPMS and SPMS can replicate the disease phenotype and provide insights in understanding repair pathways. In pilot data they have shown that injecting this cellularmaterial derived from patients with progressive disease in a mouse brain leads to typical MS lesions remote from the site of injection in areas of the spinal cord (a site of disease predilection in progressive disease). This is an extremely exciting finding and is an original discovery. Confirmatory experiments are currently being performed and will for the first time allow an animal model based on human pathology to be investigated. In addition, this also has the potential of allowing the development of therapeutic strategies specifically directed at progressive disease.
3) Dr. Brydon and colleagues have been comparing the immune profiles of treatment-unresponsive progressive disease patients with those of long duration completely benign patients who have no disability. We are doing this because immune mechanisms are universally regarded as being important in the pathogenesis of MS. Dr. Brydon hypothesizes that comparison of these two distinct populations of patients at the opposite ends of the MS disability spectrum will help identify the critical immunological factors associated with disease progression. In preliminary work, they have shown that high levels of CSF TH1 producing gamma interferon cells occur in patients with severe disease and in contrast, patients with “benign” disease have upregulated FoxP3+ regulatory T cells. This suggests that in benign patients, the body’s regulatory system promotes self tolerance and in patients with progressive disease, the innate controls on self tolerance are dysfunctional. Ongoing studies are looking at all other immune cell types and at their cellular products such as cytokines and chemokines. Upon completion of these critical studies, we may be in a position to recognize early in the disease patients who are destined for a poor outcome. This would allow therapeutic intervention of appropriate aggressiveness to be implemented prior to the development of irreversible disability.
4) Our newest avenue of research has resulted from the recruitment of Dr. Mir from University of Illinois, Chicago who joined MSRCNY in March 2011. Her expertise in cellular oxidative stress has led to initial studies in looking at isoprostanes and other oxidative stress biomarkers in patients with progressive disease.