SOD/Catalase mimics for age-related learning impairment

SOD/过氧化氢酶模拟物治疗与年龄相关的学习障碍

• 批准号: 7126436
• 负责人: SUSAN DOCTROW
• 金额: $ 67.2万
• 依托单位: PROTEOME SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126436
• 关键词: aging; animal old age; behavioral /social science research tag; brain disorder chemotherapy; catalase; chemoprevention; cognition disorders; dosage; drug administration rate /duration; drug design /synthesis /production; drug screening /evaluation; enzyme activity; high performance liquid chromatography; immunocytochemistry; laboratory mouse; laboratory rat; learning disorders; liquid chromatography mass spectrometry; neurotoxicology; nonhuman therapy evaluation; oxidative stress; pharmacokinetics; superoxide dismutase

DESCRIPTION (provided by applicant): Aging is often accompanied by a deterioration of learning and memory processes, a condition now referred to as mild cognitive impairment (MCI). Recent studies have indicated that 12% of patients afflicted with MCI will develop Alzheimer's disease, as opposed to 2% of the general population. Although the causes underlying MCI are not known, there is much evidence implicating oxidative damage. Eukarion has developed a class of low molecular weight molecules that are catalytic scavengers of reactive oxygen species (ROS), acting as mimics for the endogenous antioxidant enzymes superoxide dismutase (SOD) and catalase. These compounds are effective in many models for neurological and other classes of diseases. During Phase I of this STTR grant, two of these compounds, EUK-189 and EUK-207, were tested for their activity in preventing age-related loss of cognitive function and accumulation of oxidative stress in mice of early middle age" (8 to 11 months). Both improved cognitive performance and reduced several indicators of oxidative stress in the brain. These Phase I data support further investigation of these compounds as therapeutic agents for MCI and, potentially, for age-related neurodegenerative disease in humans. Phase II research will focus on further testing the two compounds in age-related loss of cognitive performance and on conducting key preclinical research to select one for more advanced preclinical research leading to an Investigational New Drug (IND) application for a chronic neurodegenerative disorder. Specific aims will (1) produce scale-up batches of both compounds under "near-GMP: conditions; in mice, test effects of long-term dosing, and lower doses, of compounds on (2) cognitive impairment, (3) brain oxidative stress, (4) drug and Mn levels, and (5) toxicology assessments; and (6) investigate potential chronic dosing methods for use in the clinic. (7) Based on these data, a lead compound will be selected toward the end of Phase II, and formal preclinical work will commence.

描述（由申请人提供）：衰老通常伴随着学习和记忆过程的恶化，这种情况现在被称为轻度认知障碍（MCI）。最近的研究表明，12%患有轻度认知障碍的患者会患上阿尔茨海默病，而普通人群的这一比例为2%。虽然MCI的病因尚不清楚，但有很多证据表明它与氧化损伤有关。Eukarion开发了一类低分子量分子，它们是活性氧（ROS）的催化清除剂，可以模拟内源性抗氧化酶超氧化物歧化酶（SOD）和过氧化氢酶。这些化合物在许多神经系统疾病和其他类型疾病的模型中有效。在这项STTR资助的第一阶段，研究人员测试了其中两种化合物EUK-189和EUK-207在中年早期（8至11个月）小鼠中预防与年龄相关的认知功能丧失和氧化应激积累的活性。两者都提高了认知能力，减少了大脑中氧化应激的一些指标。这些I期数据支持这些化合物作为MCI治疗剂的进一步研究，并可能用于治疗人类年龄相关的神经退行性疾病。II期研究将集中于进一步测试这两种化合物在与年龄相关的认知能力丧失中的作用，并进行关键的临床前研究，以选择一种化合物进行更高级的临床前研究，从而为慢性神经退行性疾病的研究新药（IND）申请。具体目标将是：(1)在“接近gmp”的条件下生产这两种化合物的放大批次；在小鼠中，测试长期给药和低剂量化合物对(2)认知障碍、(3)脑氧化应激、(4)药物和锰水平以及(5)毒理学评估的影响；(6)研究潜在的临床慢性给药方法。(7)基于这些数据，将在II期结束时选择先导化合物，并开始正式的临床前工作。