CYCLOPHOSPHAMIDE IN THE TREATMENT OF MULTIPLE SCLEROSIS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。多发性硬化症(MS)是一种自身免疫性疾病，其特征是中枢神经系统内髓鞘和轴突的进行性免疫破坏。尽管针对多发性硬化症患者的几种药物已经开发、批准和临床使用，但大多数患者仍继续出现进行性残疾。虽然自体干细胞移植(SCT)的免疫消融策略在某些患者中可能在阻止疾病和诱导稳定缓解方面有效，但这些策略与不可接受的死亡率相关，使大多数患者无法使用这种治疗方法。此外，长期的常规免疫调节治疗和免疫消融联合移植都是非常昂贵的治疗方法。我们建议对20名患有侵袭性复发缓解多发性硬化症(RRMS)的受试者进行为期两年的前瞻性随访研究，这些受试者不能耐受或未能对传统治疗做出最佳反应，并处于疾病进展和功能丧失的高风险中。选择参加这项研究的患者将接受一个疗程的大剂量环磷酰胺方案，而不是移植(HiCy)。之所以选择HiCy，是因为它能够在其他自身免疫性疾病中诱导长期缓解，并且与之前所有其他环磷酰胺方案不同，在HiCy女士测试的方案中，HiCy可以诱导次全免疫消融，只保留造血干细胞，从而允许在不进行骨髓移植的情况下重建免疫系统。免疫系统的这一次“重新启动”可能会从根本上改变它，减少激活的、自动反应的免疫效应细胞的存在。这项先导性研究的主要结果将是确定HiCy在这一患者群体中是否安全。具体地说，我们将确定在MS患者中使用HiCy是否比免疫消融术和SCT更安全。MS疾病活动性的替代标记物，包括MRI测量和免疫学分析，将作为次要结果进行测量。我们预测，HiCy将显著减少大脑中存在的Gd增强病变的数量，并将促进以MS为特征的免疫紊乱的“纠正”。从这项试点研究产生的数据将足以使对III期临床试验的优点做出明智的决定。如果HiCy是安全的，并导致疾病活动性的放射学和免疫学标记物的长期减少，那么随机试验将是合理的。

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.