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的方式抑制免疫系统，具有低潜在的严重副作用，并且易于给药。目前对多发性硬化症（MS）的治疗，大多数是广泛抑制免疫系统，只是部分有效，并受到副作用或频繁注射导致高度不依从性的必要性的阻碍。利用实验性自身免疫性脑脊髓炎（EAE），假设的MS动物模型，Anergix开发了一种抗原特异性基因治疗方法，其中成纤维细胞被转导分泌一种脑源性肽，当注射到患病小鼠体内时，会导致复发率的显著降低，大脑中淋巴细胞数量的显著减少，以及细胞因子谱的改变，以抗炎表型。将转导的细胞隔离在一个可植入的腔室中，允许肽表位的扩散，从而可以使用异体细胞系进行治疗。随着Anergix将这种疗法推向临床，SBIR一期项目的具体目标是：

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.