Interleukin10 Microsphere in Inflammatory Bowel Disease

细胞因子白介素10(IL-10)在治疗炎症性肠病(IBD)的临床试验中显示出良好的前景。目前，对IBD患者全身应用IL-10的方法有静脉推注或皮下注射。由于IL-10在体内的半衰期很短，需要在几周内重复注射高剂量的IL-10才能有效。在这项建议中，一种新的给药技术可以将低剂量的白介素10(IL-10)直接持续释放到胃肠道，并在IBD小鼠模型中进行测试。IL-10被包裹在可生物降解的聚合物微球中，这些微球是专门为实现对肠道上皮的强烈黏附而配制的，并被口服给IL-10基因敲除的小鼠，这些小鼠自发发展为慢性小肠结肠炎。然后，在小鼠模型的两个不同实施例中，评估从胃肠道中的生物黏附微球以持续方式释放的IL-10抑制炎症和改善疾病的能力。在目标1中，比较了负载IL-10的生物黏附微球预防幼鼠疾病发展的能力与全身注射IL-10的能力。在目的2中，评估了IL-10微球抑制成年小鼠已建立的疾病的效果，并与全身注射IL-10治疗进行了比较。如果成功，我们的新型递送系统将为IBD的治疗提供一种更具临床可行性和更有效的替代方案，以取代团注可溶性IL-10。拟议的商业应用：口服IL-10包裹的可生物降解微球用于治疗炎症性肠病的商业应用是显而易见的。如果证明有效，这种方法将提供一种简单、有效和临床上更可行的替代方案，以替代静脉注射可溶性IL-10。T&B BioClone打算与我们在布朗大学的合作者合作，将IL-10微球技术用于治疗IBD的临床应用。

The cytokine Interleukin-10 (IL-10) has shown promise in clinical trials for the treatment of inflammatory bowel disease (IBD). Currently IL-10 is administered to IBD patients systemically either by bolus intravenous or subcutaneous injections. Due to the short in vivo half-life of IL-10, repeated injections of high doses of IL-10 over a period of several weeks is required for efficacy. In this proposal, a novel delivery technology for the sustained release of low-dose Interleukin-10 (IL-10) directly to the gastrointestinal tract is tested in a murine model of IBD. IL-10 is encapsulated into biodegradable polymer microspheres which are specifically formulated to achieve a strong adhesion to the intestinal epithelium and are administered orally to IL-10 knock-out mice which spontaneously develop chronic enterocolitis. The ability of IL-10 that is released in a sustained fashion from the bioadhesive microspheres in the GI tract to suppress inflammation and ameliorate disease is then evaluated in two different embodiments of the murine model. In Aim 1, the ability of IL-10-loaded bioadhesive microspheres to prevent the development of disease is compared to that of bolus systemic IL-10 administration in young mice. In Aim 2, the efficacy of IL-10 microspheres to suppress established disease is evaluated and compared to bolus systemic IL-10 therapy in adult mice. If successful, our novel delivery system will provide a more clinically feasible and effective alternative to bolus injections of soluble IL-10 for the treatment of IBD. PROPOSED COMMERCIAL APPLICATIONS: The commercial application of orally administered IL-10-encapsulated biodegradable microspheres for treatment of inflammatory bowel disease is readily apparent. If proven effective, this approach will provide a simple, effective and more clinically feasible alternative to parenteral administration of soluble IL-10. T & B Bioclone intends to pursue the clinical use of the IL-10 microsphere technology for therapy of IBD in collaboration with our collaborators at Brown University.