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Nanocarrier-targeted mesenchymal stem cells to treat inflammatory bowel disease

纳米载体靶向间充质干细胞治疗炎症性肠病

基本信息

批准号：
9093326
负责人：
Maria Teresa Abreu
金额：
$ 23.03万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9093326
关键词：
Address Adverse effects Affect Allogenic Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Area Azathioprine Binding Biochemical Blood Vessels CD11a Antigen Cells Child Childhood Chronic Clinical Clinical Trials Colon Crohn&apos s disease Data Development Dinoprostone Disease Dose Drug Delivery Systems Epithelial Failure Fright Future Gastroenterologist Genetic Glycocalyx Growth Healed Home environment Homing Human ICAM1 gene Immunomodulators Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Infusion procedures Injection of therapeutic agent Injury Institutes Intervention Studies Intestines Lead Location Malignant Neoplasms Medical Mesenchymal Stem Cells Minority Modeling Molecular Mus Nanotechnology Natural Immunity Nitric Oxide Outcome Parents Patients Permeability Placebo Effect Plant Roots Production Property Recovery Small Intestines Sodium Dextran Sulfate Stem cells Surgeon Systemic Therapy TNF gene Testing Therapeutic Agents Time Tissues Transforming Growth Factor beta Translating Ulcer Umbilical cord structure Universities Veins Venous Work Wound Healing base cytokine early onset healing improved infliximab intercellular cell adhesion molecule interest large bowel Crohn&apos s disease mouse model multidisciplinary nanocarrier nanoparticle outcome forecast particle public health relevance repaired statistics stem cell therapy success targeted delivery traditional therapy tumorigenic

项目摘要

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.