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

项目总结 多发性硬化症(MS)是一种自身免疫性疾病，中枢神经系统内的髓鞘受到攻击， 导致250多万MS患者的运动功能衰弱。有有效的药物可用 帮助减缓多发性硬化症，但其中许多是注射制剂，患者不能再作为自我给药 它们在疾病发展过程中失去灵巧性和协调性。此外，因为多发性硬化症患者需要大量 注射次数在过去几十年中，患者经历了与注射相关的不良事件的高发。 临床研究表明，这些挑战最终会显著降低生活质量和患者的依从性。 降低多发性硬化症治疗的疗效。在生物工程研究基金(BRG)期间，我们将结合 工程专业知识、可降解微针(MN)贴片和批准的人类多发性硬化症药物 治疗多发性硬化症或耐受的MN贴片。我们将从格列塔聚醋酸酯(GA)合成MnS，它是世界上最大的 广泛使用的多发性硬化症药物。GA是由髓鞘多肽的混合物组成的。尽管被广泛使用， 然而，GA的作用机制尚不清楚。GA的髓鞘衍生成分以及新的 研究表明，GA的功能至少部分是通过引导对髓鞘的免疫反应远离炎症， 提供可能存在髓鞘特异性耐受成分的线索。在三个目标中，我们将1)描述 装载GA的MN的物理化学性质和这些货物的释放状态，以及 体外与髓鞘反应细胞的相互作用，2)评估MN在皮肤中的生物分布和诱导的耐受性， 3)表明MNS对两种MS小鼠模型(EAE、RR-1)是有效的。 EAE)。重要的是，我们的所有研究--从结构比较到疾病疗效--都将成为基准 与目前临床使用的可注射GA形式和方案相反。我们的计划得到了强劲的初步数据的支持 证实MNS可以用GA设计，在EAE和RR-EAE期间，MNS减少T细胞的浸润 中枢神经系统是有效的，即使在GA传统注射无效的剂量下也是有效的。因此， GA-MNS可以通过有效地靶向特定的皮肤常驻免疫细胞来提高依从性和疗效， 同时也创造了显著的剂量节约的可能性。在整个AIMS中，我们将使用迭代 通过反馈和设计策略，将我们研制的第一代移动通信网络改进为第二代移动通信网络。 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，并增加 通过推广到其他类别的多发性硬化症药物的健壮性。我们的工作是由我们建立的多学科促进的 该团队包括生物工程师、免疫学家和以多发性硬化症为重点的临床医生。此外，该团队还拥有 在侧重于免疫耐受性的项目上进行富有成效的合作。在金砖四国机制的支持下， 在这项提案的最后，我们将有强有力的定位，将工作推向多发性硬化症患者手中，并 这一进展可能会对患者的质量、依从性和药物疗效产生实际影响。

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.