Sustained Release Formulation for Treatment of Autoimmune Disease MS

描述（由申请人提供）：多发性硬化症（MS）是一种年轻人的炎性自身免疫性疾病，在美国影响超过530，000人，在全球影响约200万人。MS的病理特征是脑和脊髓中的炎症、脱髓鞘和轴突损伤。在这种疾病中，免疫系统错误地攻击髓鞘，进一步损害周围神经，最终使患者坐轮椅。目前FDA批准的MS疾病改善治疗，例如，β干扰素1a（Avonex（r）和Rebif（r））和1b（Betaseron（r））、醋酸格拉替雷（Copaxone（r））、米托蒽醌（Novantrone（r））和新上市的Tysabri（r）专门针对疾病的炎症期，对髓鞘修复没有明显作用。超过一半的MS患者对现有治疗反应不佳，部分原因可能是他们未能解决修复部分。因此，当人们专注于长期功能恢复时，受损轴突及其周围髓鞘的恢复，即神经再生和髓鞘再生，可能比急性炎症发作的简单缓解更重要。Cognosci创新性地创建了一种基于载脂蛋白E受体结合结构域的神经恢复策略，该结构域可以模拟apoE全蛋白的主要生物活性，并可能用于治疗相关的神经系统疾病，如MS。使用人类MS的多种动物模型，并获得了apoE-模拟的COG 112可以适当地减弱炎症反应，并促进髓鞘重建，以及体外和体内的轴突再生，表明其在临床上对MS患者的潜在效用。 为了将研究结果从实验室工作台转化为患者床边，Cognosci将开发一种临床上有利的给药制剂，允许持续释放治疗化合物。持续释放制剂的成功开发将降低给药频率，从而克服肽治疗剂通常需要的频繁给药的主要限制。完成拟议的研究是一个关键步骤，以验证这种一流的髓鞘再生治疗MS在一个更临床有利的配方，减少给药频率。 公共卫生相关性：多发性硬化症是一种毁灭性的炎症性自身免疫性疾病，影响着50万美国年轻人。这种疾病的不受控制的发展通常使受害者终身坐在轮椅上。由于MS的病因和病理非常复杂，目前市场上的MS药物仅针对疾病的炎症成分。对新疗法的需求很高。Cognosci创新性地设计了一种化合物，即COG 112，该化合物已被证明具有多种治疗MS的有利特性，不仅可以减轻炎症发作，还可以刺激受损髓鞘的重建以及断裂轴突的重新连接。该提议的目的是开发一种缓释制剂，其允许治疗剂的延长释放，因此减少了对频繁注射的需要。这是从临床前开发到临床试验的非常重要的一步。该项目的成功完成将使IND安全性/毒性研究能够启动，以获得FDA批准进行临床试验，并且是最终进入临床的必要条件。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory autoimmune disease in young adults, affecting more than 530,000 people in the United States and approximately 2 million worldwide. MS is characterized pathologically by inflammation, demyelination and axonal damage in the brain and spinal cord. In this disorder, the immune system mistakenly attacks the myelin sheath, which further damages surrounding nerves and eventually makes the patient wheelchair-bound. Current FDA-approved disease-modifying treatments for MS, e.g., beta interferon 1a (Avonex(r) and Rebif(r)) and 1b (Betaseron(r)), glatiramer acetate (Copaxone(r)), mitoxantrone (Novantrone(r)) and newly marketed Tysabri(r) specifically target the inflammatory phase of the disease and have no clear effect on myelin repair. That more than half of MS patients do not respond well to existing treatments may be due, in part, to their failure to address the reparative component. Therefore, restoration of damaged axons and their surrounding myelin sheath, namely neuroregeneration and remyelination, may be more important than simple relief of the acute inflammatory atack when one is focused on long-term functional recovery. Cognosci has innovatively created a neurorestorative strategy based on the apolipoprotein E receptor-binding domain that can mimic the major bioactivities of apoE holo-protein and can be potentially used for treatment of related neurological disorders like MS. We have identified a lead compound, COG112, using multiple animal models of human MS and have obtained proof-of- concept that the apoE-mimetic COG112 can properly attenuate inflammatory responses and facilitates myelin reconstruction, as well as axonal regeneration both in vitro and in vivo, indicating its potential utility for MS patients in the Clinic. To translate findings from lab bench to patient bedside, Cognosci will develop a clinically favorable dosing formulation that permits sustained release of the therapeutic compound. Successful development of a sustained release formulation will reduce the frequency of dosing and thus overcome the major limitation of frequent dosing typically needed for peptide therapeutics. The completion of the proposed studies is a critical step to validate this first-in-class remyelination therapy for MS in a more clinically favorable formulation that reduces the frequency of dosing. PUBLIC HEALTH RELEVANCE: Multiple Sclerosis is a devastating inflammatory autoimmune disease affecting half million young Americans. Uncontrolled progress of the disease usually put the victims on wheelchair for a life-ling time. Because MS is very complicated in etiology and pathology, the current MS drugs on the market only target on the inflammatory component of disease. Novel therapeutics is highly demanded. Cognosci has innovatively designed a compound, namely COG112, that had demonstrated multiple favorable properties for treatment of MS that can not only attenuate the inflammatory attack, but also stimulate the reconstruction of damaged myelin sheath as well as the reconnection of broken axons. The purpose of this proposal is to develop a sustained release formulation that permits extended release of therapeutic agent therefore reduces the need for frequent injection. This is a very important step from preclinical development towards clinical trials. Successful completion of this project will enable initiation of an IND safety/toxicity study to obtain FDA approval for clinical trial and is requisite for eventually bringing to clinic.