GM-CSF/sargramostim treatment to improve cognition in Down syndrome

GM-CSF/沙格司亭治疗可改善唐氏综合症的认知能力

• 批准号: 10304446
• 负责人: Huntington Potter
• 金额: $ 34.55万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304446
• 关键词: Activities of Daily Living; Adolescent; Adult; Adverse effects; Age; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein Precursor; Amyloidosis; Animal Model; Apoptotic; Biological Markers; Blood; Blood specimen; Bone Marrow; Brain Pathology; Cerebellum; Cerebrum; Child; Clinical Trials; Cognition; Cognitive; Communities; Data; Dementia; Dose; Double-Blind Method; Down Syndrome; Employment; Exhibits; FDA approved; Floor; Gene Proteins; Glial Fibrillary Acidic Protein; Granulocyte-Macrophage Colony-Stimulating Factor; Hippocampus (Brain); Human; Impaired cognition; Incidence; Individual; Intellectual functioning disability; Language; Leukocytes; Linguistics; Living Wills; Longevity; Measures; Memory; Modality; Mus; Nerve Degeneration; Nervous System Trauma; Neurologist; Neurons; Outcome Measure; Parkinson Disease; Participant; Patients; Persons; Pharmaceutical Preparations; Phase II Clinical Trials; Phase II/III Trial; Phenotype; Placebos; Plasma; Production; Quality of life; Randomized; Recombinants; Recording of previous events; Research; Research Personnel; Retrospective Studies; Safety; Spinal cord injury; Subcutaneous Injections; Tauopathies; Testing; Therapeutic; Traumatic Brain Injury; Treatment Factor; Visit; Vulnerable Populations; Wild Type Mouse; Work; aged; amyloid pathology; astrogliosis; base; cerebral amyloidosis; chemobrain; circulating biomarkers; cognitive ability; cognitive benefits; cognitive enhancement; cognitive function; cognitive performance; cognitive testing; design; enhancing factor; executive function; experience; follow-up; frontal lobe; hematopoietic cell transplantation; improved; leukemia; meetings; mental state; motor control; mouse model; multidisciplinary; nervous system disorder; neuroinflammation; normal aging; novel therapeutics; patient population; primary endpoint; primary outcome; processing speed; safety testing; sargramostim; secondary outcome; severe intellectual disability; single molecule; stroke model; subcutaneous; tau Proteins; treatment duration; young adult

PROJECT SUMMARY/ABSTRACT People with Down syndrome (DS) exhibit significant hypoplasia of the frontal lobe, hippocampus, and cerebellum and mild to severe intellectual disability, which challenges their ability to function independently. Any enhancement of their cognitive ability would greatly improve their quality of life and activities of daily living, but currently there are no therapeutics available for enhancing cognitive function in people with DS. This proposal aims to design and complete a clinical trial in adults with DS using recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF/sargramostim), an FDA-approved drug for increasing the production and differentiation of various white blood cells with almost 30 years of excellent safety history in numerous patient populations. In a previous retrospective study, we found that sargramostim treatment is associated with cognitive improvements in leukemia patients after bone marrow chemoablation and hematopoietic cell transplantation. In a recently concluded Phase II clinical trial (NCT01409915), we found that three weeks of sargramostim treatment was safe and well tolerated in mild-to-moderate Alzheimer’s disease (AD) participants and was associated with improvement in the MMSE, reduced biomarkers of neurodegeneration (Tau and UCH-L1), but no evidence of reduced amyloid. Furthermore, we have found that treatment with murine GM-CSF improves cognition and ameliorates astrogliosis in a mouse model of DS (which has no AD pathology), that it rapidly reverses cognitive impairment and removes some cerebral amyloid pathology in mouse models of AD, and that it improves age- related cognitive decline in aged wild-type mice. Numerous other studies have shown that GM-CSF is neuroprotective, anti-apoptotic, neurogenic, and beneficial in several neurological diseases and injuries, for example, in a clinical trial with Parkinson’s disease subjects and in animal models of stroke, spinal cord injury, and traumatic brain injury. Specifically, this proposal is designed to investigate whether treatment with sargramostim at the FDA-recommended dose is safe and tolerable in adults with DS, whether it can improve measures of cognitive function, quality of life, and activities of daily living, and whether it can reduce the Tau and UCH-L1 biomarkers in the blood that we have shown to evidence neuroinflammation and neurodegeneration in people with DS and to be reduced in AD patients by GM-CSF treatment.

项目摘要/摘要 患有唐氏综合症（DS）的人暴露了额叶，海马和小脑的明显发育不全 和轻度至重度智力残疾，这挑战了他们独立运作的能力。任何 增强其认知能力将大大改善其日常生活的生活质量和活动，但 目前，尚无治疗剂可增强DS患者的认知功能。这个建议 旨在使用重组人粒细胞巨噬细胞设计和完成DS成人的临床试验 菌落刺激因子（GM-CSF/Sargramostim），一种由FDA批准的药物，用于增加产量和 众多患者的各种白血细胞的分化与近30年的出色安全历史 人群。在先前的回顾性研究中，我们发现sargramostim治疗与认知有关 骨髓化疗和造血细胞移植后白血病患者的改善。在 最近结束的II期临床试验（NCT01409915），我们发现三周的Sargramostim处理 在轻度至中度的阿尔茨海默氏病（AD）参与者中安全且容忍良好，并且与 改善MMSE，减少神经退行性的生物标志物（TAU和UCH-L1），但没有证据表明 淀粉样蛋白减少。此外，我们发现用鼠GM-CSF治疗可改善认知和 在DS的小鼠模型（没有AD病理学）的小鼠模型中改善星形胶质病，它迅速逆转了认知 损伤并去除AD小鼠模型中的一些脑淀粉样病理学，并改善了年龄 - 老化的野生型小鼠的相关认知能力下降。许多其他研究表明，GM-CSF是 神经保护性，抗凋亡，神经源性和有益于几种神经系统疾病和损伤 例如，在帕金森氏病和中风的动物模型，脊髓损伤的临床试验中 和脑损伤。特别是，该提案旨在调查是否处理 FDA征用剂量的sargramostim在成人DS的成年人中是安全可容忍的，它是否可以改善 认知功能，生活质量和日常生活活动的度量，以及是否可以减少tau和 我们已经证明了血液中的UCH-L1生物标志物，证明了神经炎症和神经变性 通过GM-CSF治疗，DS患者在AD患者中减少。