Sustained Release Formulation for Treatment of Autoimmune Disease MS

用于治疗自身免疫性疾病 MS 的缓释制剂

• 批准号: 8057567
• 负责人: FENG-QIAO LI
• 金额: $ 27.91万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057567
• 关键词: Acute; Address; Affect; American; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apolipoprotein E; Attenuated; Autoimmune Diseases; Axon; Behavior; Binding; Biotechnology; Brain; Canis familiaris; Cardiac; Cells; Cerebellum; Clinic; Clinical Trials; Copaxone; Cuprizone; Data; Demyelinations; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Equipment and supply inventories; Etiology; Experimental Autoimmune Encephalomyelitis; FDA approved; Failure; Frequencies; Funding; Generations; Goals; Grant; Human; Immune System Diseases; In Vitro; Industry; Inflammation; Inflammatory; Inflammatory Response; Injectable; Injection of therapeutic agent; Interferon beta-1a; Interferon-beta; Intramuscular; Intravenous; LDL-Receptor Related Protein 1; Laboratories; Laboratory Finding; Lead; Life; Lysophosphatidylcholines; Marketing; Medical; Medicine; Microscopic; Mitoxantrone; Mitroxone; Modeling; Multiple Sclerosis; Mus; Myelin; Myelin Basic Proteins; Myelin Sheath; Natural regeneration; Nerve; Nerve Crush; Oligodendroglia; Oral; Pathology; Patients; Peptides; Peripheral Nerves; Pharmaceutical Preparations; Pharmacodynamics; Phase; Property; Proteins; Proteolipids; Rattus; Recombinant interferon beta-1b; Recovery of Function; Relapse; Relapsing-Remitting Multiple Sclerosis; Safety; Series; Serum; Slice; Small Business Innovation Research Grant; Spinal Cord; Subarachnoid Hemorrhage; Subcutaneous Injections; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Translating; Traumatic Brain Injury; Treatment Efficacy; Tysabri; United States; Wheelchairs; Wound Healing; avonex; axon regeneration; base; body system; clinically relevant; copolymer 1; design; effective therapy; efficacy testing; excitotoxicity; human disease; in vivo; in vivo Model; interest; mimetics; mouse model; nervous system disorder; neurorestoration; novel; novel strategies; novel therapeutics; oligodendrocyte-myelin glycoprotein; pre-clinical; receptor binding; reconstruction; repaired; restoration; safety study; sciatic nerve; subcutaneous; young adult

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.

描述（由申请人提供）：多发性硬化症（MS）是年轻人的一种炎症自身免疫性疾病，影响了美国超过530,000人，在全球范围内约有200万人。 MS在病理学上以炎症，脱髓鞘和脊髓的轴突损伤为特征。在这种疾病中，免疫系统错误地攻击了髓鞘，这进一步损坏了神经周围的鞘，并最终使患者轮椅结合。当前对MS的FDA批准的疾病改良治疗方法，例如β1A（Avonex（R）和Rebif（R）和1B（betaseron（r）），乙酸盐（copaxone（r）（copaxone（r）），Mitoxantrone（Novantrone（r）和新的疾病均具有针对性的tyys the tysbiri（r），tyysbiri（r）（betaseron（r）（r）（r）（r）（copaxone（r））髓鞘修复。超过一半的MS患者对现有治疗的反应不佳可能部分是由于他们无法解决赔偿成分。因此，恢复受损的轴突及其周围的髓鞘鞘，即神经创造和透明度，当人们专注于长期功能恢复时，可能比简单缓解急性炎症性ATACK的简化更为重要。 Cognosci创建了一种基于载脂蛋白E受体结合领域的神经训练策略，该策略可以模仿ApoE Holo蛋白的主要生物活性，并有可能用于治疗MS等相关神经系统疾病。我们已经使用人类MS的多种动物模型确定了铅化合物COG112，并获得了概念证明，即apoe-Mimetic Cog112可以适当地衰减炎症反应并促进髓磷脂的重建，并促进轴突重建，以及在体外和体内的轴突再生。 为了将发现从实验室长凳转换为患者的床边，Cognosci将开发一种临床上有利的给药配方，允许持续释放治疗化合物。成功开发持续的释放配方将降低给药的频率，从而克服通常通常需要用于肽疗法所需的频繁给药的主要局限性。拟议研究的完成是在更临床上有利的配方中验证MS的这种第一类延期治疗的关键步骤，从而降低了给药频率。 公共卫生相关性：多发性硬化症是一种毁灭性的炎症自身免疫性疾病，影响了50万美国人。这种疾病的不受控制的进展通常使受害者坐在轮椅上生活。由于MS在病因和病理学方面非常复杂，因此市场上当前的MS药物仅针对疾病的炎症成分。高度要求新颖的治疗学。 Cognosci创新设计了一种化合物，即COG112，该化合物表现出了多种有利的特性来治疗MS，不仅可以减弱炎症性攻击，还可以刺激受损受损的髓鞘鞘的重建以及重新连接破裂的轴突。该提案的目的是开发一种持续的释放公式，允许扩展治疗剂的释放，因此减少了频繁注射的需求。这是从临床前发展到临床试验的非常重要的一步。该项目的成功完成将启动IND安全/毒性研究，以获得FDA批准进行临床试验，这对于最终带入诊所是必需的。