Cell-based Gene Therapy for Multiple Sclerosis

描述（由申请人提供）：该项目的长期目标是开发一种治疗自身免疫性疾病多发性硬化症（MS）的方法，该方法将以抗原特异性方式抑制免疫系统，严重副作用的可能性较低，并且易于管理。目前对多发性硬化症（MS）的治疗，其中大部分广泛抑制免疫系统，只是部分有效，并受到副作用或频繁注射的必要性的阻碍，导致高度的不依从性。使用实验性自身免疫性脑脊髓炎（EAE）（MS的假定动物模型），Anergix开发了一种抗原特异性基因治疗，其中将经转导以分泌脑肽的成纤维细胞注射到患病小鼠中时，可导致复发率显著降低，脑中淋巴细胞数量显著减少，以及细胞因子谱改变为抗炎表型。将转导的细胞隔离在允许肽表位扩散的可植入室中使得能够使用同种异体细胞系进行治疗。随着Anergix将这种疗法推向临床，SBIR I期项目的具体目标是： * 确定明显的免疫改变，特别是抗炎反应的证据，这可以归因于我们的治疗，并可用于临床试验以监测安全性， * 生成并表征将构成Anergix治疗的分泌MBP肽的人成纤维细胞（MRC 5-MBP） 免疫研究将在SJL/J EAE模型中进行，并将研究髓鞘抗原特异性增殖和肽回忆细胞因子应答。用荧光素酶基因转导的MRC 5细胞的体内生物发光成像将用于表征包封的转导细胞的增殖、寿命和存活性，并且质谱法将用于测量分泌的肽。在这些研究结束时，我们将确定受我们用于治疗多发性硬化症的基于细胞的疗法影响的免疫参数，并且还表征了我们计划在1期临床试验中使用的治疗性细胞系（里程碑）。在这一点上，我们将提交SBIR II期申请，解决治疗性主细胞库的生产，以及使用该细胞库的动物毒理学和致瘤性研究。这些研究是FDA在2007年11月Anergix pre-IND会议期间要求进行的。 公共卫生相关性：目前可用的MS疾病修饰疗法（DMT）有许多缺点，包括频繁注射和副作用，这限制了其市场渗透率，并导致异常高的不依从率。12，13超过三分之一的MS患者在12-18个月内停止服用DMT。Anergix正在为临床开发的低剂量抗原特异性治疗有望减少副作用，减轻更频繁治疗的负担，从而提高患者的依从性，从而在患者的一生中实现更好的疾病管理。

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a treatment for the autoimmune disease multiple sclerosis (MS) that will suppress the immune system in an antigen-specific manner, has a low potential for serious side effects, and is easy to administer. Current treatments for multiple sclerosis (MS), most of which broadly suppress the immune system, are only partially effective and encumbered by side effects or the necessity for frequent injections that leads to a high degree of non-compliance. Using experimental autoimmune encephalomyelitis (EAE), the putative animal model of MS, Anergix developed an antigen-specific gene therapy treatment, in which fibroblasts, transduced to secrete an encephalogenic peptide, when injected into sick mice, cause a dramatic reduction in relapse rate and a profound decrease in the number of lymphocytes in the brain, as well as an alteration in the cytokine profiles to an anti-inflammatory phenotype. Sequestering the transduced cells within an implantable chamber that allowed diffusion of the peptide epitope enabled the use of an allogeneic cell line for therapy. As Anergix moves this therapy towards the clinic, the specific aims of this SBIR Phase I project are: * to identify overt immune alterations, particularly evidence of an anti-inflammatory response, that can be attributed to our therapy and that can be used in a clinical trial to monitor for safety, * to generate and characterize the MBP peptide-secreting human fibroblasts (MRC5-MBP) that will constitute Anergix's therapy Immune studies will be conducted in the SJL/J EAE model and will investigate myelin antigen-specific proliferation and peptide recall cytokine responses. In vivo bioluminescent imaging of MRC5 cells transduced with the luciferase gene will be used to characterize the proliferation, lifespan and survivability of encapsulated transduced cells and mass spectrometry will be used to measure secreted peptide. At the conclusion of these studies, we will have identified immune parameters that are influenced by our cell-based therapy for the treatment of multiple sclerosis, and also characterized the therapeutic cell line we plan to use in a phase 1 clinical trial (milestone). At this point, we will submit an SBIR Phase II application addressing production of a therapeutic Master Cell Bank, and animal toxicology and tumorgenicity studies using this cell bank. These studies were requested by the FDA during the Anergix pre-IND meeting in November 2007. PUBLIC HEALTH RELEVANCE: Currently available disease modifying therapies (DMTs) for MS have many drawbacks including frequent injections and side effects which have limited their market penetration and led to unusually high non-compliance rates.12,13 More than one-third of MS patients stop taking DMTs within 12-18 months. The low dose antigen specific therapy that Anergix is developing for the clinic promises to reduce side effects, reduce the burden of more frequent treatments, and thereby improve patient compliance, leading to better disease management over the lifetime of the patient.