Nanocarrier-targeted mesenchymal stem cells to treat inflammatory bowel disease

 描述（由申请人提供）：由于间充质干细胞（MSC）的抗炎特性，如分泌TGFβ、PGE2和一氧化氮，已提出将其作为炎症性肠病（IBD），特别是克罗恩病（CD）的替代有益疗法。此外，它们被认为是有组织损伤的区域的家园。CD的特征通常是小肠和结肠中的深度溃疡，并且具有深度结肠溃疡的患者具有更差的预后。虽然医学治疗是针对试图实现粘膜愈合，这是一个少数的病人， 粘膜完全愈合。因此，迫切需要改善这些统计数据的疗法。理想情况下，患者希望治疗旨在治愈，并且可以在疾病复发时间歇使用，而不是使用慢性治疗。MSC已经在CD的各种情况下进行了尝试。它们已用于肛周瘘管病患者的局部注射，以及CD的全身治疗。患者在临床试验中接受了同种异体MSC，但不幸的是，安慰剂反应率极高。另一项研究使用脐带静脉干细胞，但由于干细胞输注引起的静脉并发症，该试验提前停止。在这两种情况下，剩下的问题之一是确定缺乏效果是否是由于缺乏这些干细胞对肠道的特异性靶向，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，由于这些是干细胞，它们可能在不同的位置成为致瘤性。为了克服干细胞的上述潜在负面影响，我们的目标是测试MSC靶向递送到肠道是否会导致有效的治疗。 IBD的安全治疗。具体来说，我们将研究在小鼠模型中，纳米颗粒靶向的MSC在IBD的治疗中是否比非靶向的MSC更有益。我们假设，通过将MSC靶向肠道血管，我们将减少炎症并缩短恢复时间。我们认为，从机制上讲， 这些细胞在感兴趣的组织中，以及通过这些细胞局部产生生长因子如TGFβ。我们选择使用ICAM配体作为靶向分子靶向MSC，因为ICAM及其结合伴侣在发炎的IBD肠中的高表达。

 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.