Nanocarrier-targeted mesenchymal stem cells to treat inflammatory bowel disease

 描述(申请人提供)：间充质干细胞(MSCs)已被建议作为炎症性肠病(IBD)，特别是克罗恩病(CD)的替代有益疗法，因为它们具有抗炎特性，如分泌转化生长因子β、前列腺素E_2和一氧化氮。此外，它们被认为是组织受损区域的家园。CD的特点通常是小肠和结肠的深度溃疡，深结肠溃疡的患者预后较差。虽然医学治疗的目的是试图实现粘膜愈合，但只有少数患者能够实现 粘膜完全愈合。因此，迫切需要改善这些统计数据的治疗方法。理想情况下，患者希望进行旨在治愈的治疗，当疾病复发时可以间歇性地使用，而不是使用慢性治疗。在CD中，MSCs已经在不同的背景下进行了尝试。它们已被用于肛周瘘管病患者的局部注射，以及CD的系统治疗。患者在临床试验中接受了异基因MSCs，但不幸的是，安慰剂应答率极高。另一项研究使用了脐带静脉干细胞，但由于干细胞输注引起的静脉并发症，试验提前停止。在这两种情况下，剩下的一个问题是确定缺乏效果是否是因为缺乏这些干细胞对肠道的特定靶向，这导致需要给予高剂量的细胞，以便只有少数细胞最终回到肠道。MSC治疗的另一个问题涉及干细胞是否到达肠道以外的其他组织，由于这些组织是干细胞，它们可能会在不同的位置致癌。为了克服上述干细胞的潜在负面影响，我们的目标是测试将MSCs靶向输送到肠道是否会产生有效的 IBD的安全治疗。具体地说，我们将研究在小鼠模型中，纳米靶向MSCs是否比非靶向MSCs在治疗IBD方面更有利。我们假设，通过将MSCs靶向肠道血管系统，我们将减少炎症并缩短恢复时间。我们相信，从机制上讲，这将通过增加可获得性实现 这些细胞在感兴趣的组织中，以及通过局部产生生长因子，如转化生长因子β由这些细胞。我们选择以ICAM配体作为靶向分子作为靶向MSCs，是因为ICAM及其结合伙伴在炎症性肠病的肠道中高表达。

 DESCRIPTION (provided by applicant): Mesenchymal stem cells (MSCs) have been proposed as alternative beneficial therapies for inflammatory bowel disease (IBD), in particular in Crohn's disease (CD), because of their anti-inflammatory properties, such as secretion of TGFβ, PGE2, and nitric oxide. Moreover, they are thought to home to areas where there is tissue damage. CD is characterized often by deep ulcerations in the small intestine and in the colon and patients with deep colonic ulcerations have a worse prognosis. Although medical therapy is directed at trying to achieve mucosal healing, it is a minority of patients that achieve complete mucosal healing. Therefore, there is a critical need for therapies that will improve these statistics. Ideally, patients want therapies directed at healing and that can be used intermittently when the disease recurs, rather than using a chronic treatment. MSCs have been tried in a variety of contexts in CD. They have been used in local injections in patients with perianal fistulizing disease, as well as in systemic therapy for CD. Patients received allogeneic MSCs in a clinical trial, but, unfortunately, there was an extremely high placebo response rate. Another study used umbilical cord vein stem cells, but the trial was stopped early because of venous complications from the stem cell infusion. In both cases, one of the issues remaining is determining whether the lack of effect is due to lack of specific targeting of these stem cells to the gut, which results in need for administration of high doses of cells in order for just few to ultimately home to the intestine. Another concern of MSC therapy relates to whether stem cells reach other tissues beyond the intestine, and since these are stem cells, they may become tumorigenic in a different location. To overcome the aforementioned potential negative effects of stem cells, we aim to test whether targeted delivery of MSCs to the gut will result in an effective safe therapy for IBD. Specifically, we will investigate if nanoparticle-targeted MSCs will be more beneficial than non-targeted MSCs in the treatment of IBD in murine models. We hypothesize that by targeting MSCs to the gut vasculature we will decrease inflammation and shorten the time to recovery. We believe that mechanistically this will occur through increased availability of these cells in the tissue of interest, as well as through local production of growth factors such a TGFβ by these cells. We have chosen to target MSCs employing the ICAM ligand as the targeting molecule because of the high expression of ICAM and its binding partners in the inflamed IBD intestine.