This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Multiple sclerosis (MS) is an autoimmune disease characterized by progressive immune-mediated destruction of myelin and axons within the CNS. Despite the development, approval and clinical utilization of several medicines for patients with MS, most patients continue to accrue progressive disability. Although immunoablation strategies with autologous stem cell transplantation (SCT) may be effective in some patients in halting disease and inducing stable remission, these strategies are associated with unacceptable mortality rates, precluding the use of this treatment in most patients. Additionally, long-term conventional immunomodulatory treatment and immune ablation with transplantation are exceedingly expensive therapies. We propose a prospective two-year follow-up study in 20 subjects with aggressive relapsing-remitting MS (RRMS) who are unable to tolerate or have failed to optimally respond to conventional therapy and are at high risk of disease progression and loss of function. Patients who elect to enter the study will be given a single course of high-dose, cyclophosphamide regimen without transplantation (HiCy). HiCy has been chosen because it is capable of inducing long-term remission in other autoimmune diseases and is distinct from all other previous cyclophosphamide regimens tested in MS. HiCy may induce subtotal immune ablation, sparing only the hematopoietic stem cells, thus allowing reconstitution of the immune system without bone marrow transplantation. This one time 'rebooting' of the immune system may fundamentally alter it, diminishing the presence of activated, auto-reactive immune effector cells. The primary outcome of this pilot study will be to determine if HiCy is safe in this patient population. Specifically, we will determine whether HiCy administration is safer than immunoablation with SCT in MS patients. Surrogate markers of MS disease activity, including MRI measures and immunologic assays, will be measured as secondary outcomes. We predict that HiCy will markedly diminish the number of gadolinium enhancing lesions present in the brain and will facilitate a 'correction' in the immune derangements that characterize MS. Data generated from this pilot study will be sufficient to allow an informed decision on the merit of a phase III clinical trial. If HiCy is safe and induces a long-term reduction in radiologic and immunologic markers of disease activity, then a randomized trial would be warranted.
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