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

项目摘要 多发性硬化症（MS）是一种自身免疫性疾病，其中中枢神经系统的髓鞘受到攻击， 导致超过250万MS患者的运动功能丧失。有效的药物是可用的 帮助减缓MS，但其中许多是可注射制剂，患者不能再自我管理， 他们在疾病发展过程中失去灵活性和协调性。此外，由于MS患者需要大量的 随着几十年来注射次数的增加，患者经历注射相关不良事件的发生率很高。 临床研究表明，这些挑战最终会显著降低生活质量和患者依从性 降低MS治疗的功效。在生物工程研究资助（BRG）期间，我们将联合收割机 工程专业知识，可降解微针（MN）贴片，和批准的人类MS药物， 用于治疗MS或耐受性的MN贴剂。我们将从醋酸格拉替雷（GA）合成MN， 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。尽管广泛使用， 然而，GA的作用机制尚不清楚。GA的髓鞘衍生成分，沿着新的 揭示GA功能的研究至少部分是通过引导免疫应答远离炎症的髓鞘， 提供了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 载有GA的MN的理化性质和这些货物的释放状态，以及 与髓鞘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MS的两种小鼠模型（EAE，RR- EAE）。重要的是，我们所有的研究--从结构比较到疾病疗效--都将以 与目前临床上使用的可注射GA形式和方案相比。我们的计划得到了有力的初步数据的支持 证实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GA通过传统注射给药无效的剂量下也是有效的。因此，在本发明中， GA-MN可以通过有效靶向专门的皮肤驻留免疫细胞来提高依从性和功效， 同时也产生了显著剂量节省的可能性。在整个目标中，我们将使用迭代 反馈和设计策略，我们开发的第一代MN改进为第二代MN。 这些原型将整合可调释放技术，以进一步提高患者的依从性，并增加 通过扩展到其他类别的MS药物的稳健性。我们的工作是由我们建立的多学科促进 该团队包括生物工程师，免疫学家和以MS为重点的临床医生。此外，该团队有一个历史， 在重点关注免疫耐受的项目上开展富有成效的合作。在BRG机制的支持下， 在这项提案结束时，我们将有强大的定位，将工作推向MS患者手中， 这一进步可能对患者质量、依从性和药物疗效产生真实的影响。

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.