Engineered Induction of a Stem Cell Homing Response

 描述（由申请人提供）：间充质干细胞（MSC）是基于细胞的治疗的有希望的候选者，主要是由于其有效的免疫抑制分泌组。MSC显示出抑制T细胞、B细胞、自然杀伤细胞和抗原呈递细胞的炎症反应，使得它们在治疗多发性硬化（MS）方面特别有意义。MS影响全球250万人，是一种悲惨的神经退行性疾病，由大脑和脊髓中的适应性和先天性自身免疫炎症反应介导。MS最初遵循复发-缓解过程（RRMS），其中大多数患者最终发展为继发性进行性MS（SPMS），其特征在于中枢神经系统（CNS）损伤的进行性和不可逆积累，并且对此没有治疗。虽然MSC在MS临床前和临床研究中显示出有益的作用，由MSC分泌的神经保护和抗炎因子促进，但这种作用受到全身施用的MSC对发炎的脑和脊髓的不良归巢的限制。因此，需要增强MSC的归巢和免疫抑制特性，以提高其用于MS治疗的临床潜力。实现这一点的一种潜在方法是mRNA转染，我们最近使用该方法来利用全身施用的MSC作为细胞载体，用于将白细胞介素-10（IL-10）靶向递送至局部炎症部位，从而显著抑制炎症。 在这项提案中，我们的目标是开发一种mRNA指导的治疗性细胞平台来治疗RR和SPMS。我们假设，与CNS特异性归巢配体的mRNA转染将使我们能够靶向全身给药的MSC MS患病的脑和脊髓，增加局部水平的MSC分泌的神经营养和免疫调节可溶性因子在CNS中。通过用另外的治疗性细胞因子如IL-10、IFN-γ和IL-27同时刺激MSC，我们将使用输注的MSC作为将多种治疗因子靶向递送至发炎CNS的载体。通过这种方法，我们的目标是实现mRNA转染的治疗因子与MSC固有分泌的强效免疫抑制剂和神经保护剂之间的协同作用。我们设想这种方法将使我们能够开发一种有效的细胞平台，该平台将靶向先天性和适应性免疫反应，可能为RR和SPMS提供有效的治疗。

 DESCRIPTION (provided by applicant): Mesenchymal stem cells (MSCs) are promising candidates for cell-based therapy, mostly owing to their potent immunosuppressive secretome. MSCs were shown to suppress T cells, B cells, natural killer cells and antigen-presenting cells inflammatory responses, making them of particular interest to treat multiple sclerosis (MS). MS, effecting 2.5M people worldwide, is a tragic neurodegenerative disease, mediated by adaptive and innate autoimmune inflammatory responses in the brain and spinal cord. MS initially follows a relapsing- remitting course (RRMS), with majority of patients eventually developing secondary progressive MS (SPMS), characterized by a progressive and irreversible accumulation of central nervous system (CNS) damage, and for which there is no therapy. While MSCs show beneficial effects in MS preclinical and clinical studies, promoted by MSC-secreted neuroprotective and anti-inflammatory factors, this effect is limited by the poor homing of systemically administered MSCs to inflamed brain and spinal cord. Hence, there exists a need to augment the homing and immunosuppressive properties of MSCs to boost their clinical potential for MS therapy. A potential approach to accomplish this is mRNA transfection, which we have recently used to harness systemically administered MSCs as cellular vehicles for targeted delivery of interleukin-10 (IL-10) to sites of local inflammation, resulting in significan suppression of inflammation. In this proposal, we aim to develop an mRNA-guided therapeutic cellular platform to treat RR and SPMS. We hypothesize that mRNA transfection with CNS-specific homing ligands would enable us to target systemically administered MSCs to MS-diseased brain and spinal cord, increasing local levels of MSC-secreted neurotrophic and immunomodulatory soluble factors in the CNS. By simultaneously transfecting MSCs with additional therapeutic cytokines, such as IL-10, IFN-ß and IL-27, we will use the infused MSCs as vehicles for targeted delivery of multiple therapeutic factors to the inflamed CNS. Via this approach, we aim to achieve synergism between the mRNA-transfected therapeutic factors and the potent immunosuppressive and neuroprotective agents inherently secreted by MSCs. We envision that this approach would enable us to develop a potent cellular platform that would target both innate and adaptive immune responses, potentially providing an effective treatment for RR and SPMS.