CYCLOPHOSPHAMIDE IN THE TREATMENT OF MULTIPLE SCLEROSIS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。多发性硬化症（MS）是一种自身免疫性疾病，其特征在于CNS内髓鞘和轴突的进行性免疫介导的破坏。尽管开发、批准和临床使用了几种用于MS患者的药物，但大多数患者继续累积进行性残疾。尽管自体干细胞移植（SCT）的免疫消融策略在某些患者中可能有效地阻止疾病并诱导稳定缓解，但这些策略与不可接受的死亡率相关，因此无法在大多数患者中使用这种治疗。此外，长期的常规免疫调节治疗和免疫消融与移植是非常昂贵的治疗。我们提出了一项为期两年的前瞻性随访研究，在20名患者的侵袭性复发缓解型MS（RRMS）谁是不能耐受或未能最佳响应传统治疗，并在疾病进展和功能丧失的高风险。选择进入研究的患者将接受单疗程的高剂量环磷酰胺方案，不进行移植（HiCy）。选择HiCy是因为它能够诱导其他自身免疫性疾病的长期缓解，并且与MS中测试的所有其他先前环磷酰胺方案不同。HiCy可以诱导次全免疫消融，仅保留造血干细胞，从而允许在没有骨髓移植的情况下重建免疫系统。 免疫系统的这一次“重启”可能会从根本上改变它，减少激活的自身反应性免疫效应细胞的存在。该初步研究的主要结局将是确定HiCy在该患者人群中是否安全。具体而言，我们将确定HiCy给药是否比MS患者SCT免疫消融更安全。MS疾病活动的替代标志物，包括MRI测量和免疫学测定，将作为次要结局进行测量。我们预测HiCy将显著减少脑中存在的钆增强病变的数量，并将促进表征MS的免疫紊乱的“校正”。从该试点研究产生的数据将足以允许对III期临床试验的优点做出明智的决定。如果HiCy是安全的，并诱导疾病活动的放射学和免疫学标志物的长期减少，那么就有必要进行随机试验。

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.