Improving multiple sclerosis patient quality of life using microneedle patches to simplify delivery of MS drugs

项目概要 多发性硬化症（MS）是一种自身免疫性疾病，中枢神经系统的髓鞘质受到攻击， 导致超过 250 万多发性硬化症患者运动功能严重丧失。有效的药物是可用的 帮助减缓多发性硬化症，但其中许多是注射制剂，患者无法再自行注射，因为 他们在疾病进展过程中失去灵活性和协调性。此外，由于多发性硬化症患者需要大量 几十年来，由于注射次数较多，患者经历注射相关不良事件的发生率很高。 临床研究表明，这些挑战最终会显着降低生活质量和患者的依从性 降低多发性硬化症治疗的功效。在生物工程研究补助金 (BRG) 期间，我们将结合 工程专业知识、可降解微针 (MN) 贴片和经批准的人类多发性硬化症药物来构建第一个 MN 贴片用于治疗多发性硬化症或耐受性。我们将从醋酸格拉替雷 (GA) 合成 MN，GA 是最常用的材料之一。 广泛使用的多发性硬化症药物。 GA 由髓磷脂肽的混合物组成。尽管被广泛使用， 然而，GA的作用机制尚不清楚。 GA 的髓磷脂成分，以及新的 研究揭示 GA 的功能至少部分是通过引导对髓磷脂的免疫反应远离炎症， 提供线索可能存在髓磷脂特异性耐受的成分。跨越三个目标，我们将 1) 描述 装载 GA 的理化特性或 MN 以及这些货物的释放状态，以及 与髓磷脂反应性细胞的体外相互作用，2) 评估皮肤中的生物分布和 MN 诱导的耐受性， 淋巴结和脾脏，以及 3) 显示 MN 在两种 MS 小鼠模型（EAE、RR- EAE）。重要的是，我们所有的研究——从结构比较到疾病疗效——都将进行基准测试 反对目前临床使用的注射 GA 形式和方案。我们的计划得到了强有力的初始数据的支持 确认 MN 可以用 GA 设计，并且在 EAE 和 RR-EAE 期间，MN 减少 T 细胞浸润 即使在传统注射 GA 无效的剂量下，该药物也能有效地作用于中枢神经系统。因此， GA-MN 可以通过有效地针对专门的皮肤驻留免疫细胞来提高依从性和功效， 同时还创造了显着节省剂量的可能性。在整个目标中，我们将使用迭代 我们开发的第一代 MN 被改进为第二代 MN 的反馈和设计策略。 这些原型将集成可调释放技术，以进一步提高患者的依从性，并提高 通过扩展到其他类别的多发性硬化症药物的稳健性。我们建立的多学科促进了我们的工作 该团队包括生物工程师、免疫学家和专注于多发性硬化症的临床医生。此外，该团队还拥有以下历史： 在免疫耐受项目上开展富有成效的合作。在BRG机制的支持下， 在本提案结束时，我们将有强有力的定位，将这项工作推向多发性硬化症患者手中， 可能对患者质量、依从性和药物疗效产生真正影响的进步。

PROJECT SUMMARY Multiple sclerosis (MS) is an autoimmune disease in which myelin lining the central nervous system is attacked, leading to a debilitating loss of motor function in the more than 2.5M people with MS. Effective drugs are available to help slow MS, but many of these are injectable formulations that patients can no longer self-administer as they lose dexterity and coordination during disease progression. Further, because MS patients require a large number of injections over decades, patients experience a high incidence of injection-related adverse events. Clinical studies reveal these challenges significantly decrease quality of life and patient compliance, ultimately reducing the efficacy of MS therapies. During this Bioengineering Research Grant (BRG) we will combine engineering expertise, degradable microneedle (MN) patches, and approved human MS drugs to build the first MN patches for treating MS or tolerance. We will synthesize MNs from glatiramer acetate (GA), one of the most widely-prescribed MS drugs. GA is comprised of a mixture of myelin peptides. Despite wide-spread usage, however, the functional mechanism of GA is unclear. The myelin-derived composition of GA, along with new studies revealing GA functions at least in part by directing immune response to myelin away from inflammation, provide clues there may be a component of myelin-specific tolerance. Across three aims, we will 1) characterize the physiochemical properties or MNs loaded with GA and the states these cargos are released in, as well as the in vitro interactions with myelin-reactive cells, 2) assess biodistribution and MN-induced tolerance in skin, lymph nodes, and spleen, and 3) show MNs are efficient and efficacious in two mouse models of MS (EAE, RR- EAE). Importantly, all of our studies – from structural comparisons to disease efficacy – will be benchmarked against the current injectable GA form and regimen used clinically. Our plans are supported by strong initial data confirming MNs can be designed with GA, and that during EAE and RR-EAE, MNs reduce T cell infiltration to the CNS and are efficacious, even at doses where GA administered by traditional injections in ineffective. Thus, GA-MNs could improve compliance and efficacy by efficiently targeting specialized skin-resident immune cells, while also creating the possibility of significant dose sparing. Throughout the aims, we will use an iterative feedback and design strategy by which the 1st Generation MNs we develop are improved to 2nd Generation MNs. These prototypes will integrate tunable release technology to further improve patient compliance, and increase robustness by extension to other classes of MS drugs. Our work is facilitated by our established multidisciplinary team that includes bioengineers, immunologists, and MS-focused clinicians. Further, the team has a history of productive collaboration on projects focused on immune tolerance. With support from the BRG mechanism, by the end of this proposal we will have strong positioning to push the work toward the hands of MS patients, an advance that could have a real impact on patient quality, compliance, and drug efficacy.