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.

项目概要/摘要 唐氏综合症 (DS) 患者的额叶、海马体和小脑明显发育不全 轻度至重度智力障碍，这挑战了他们的独立运作能力。 认知能力的增强将极大地改善他们的生活质量和日常生活活动，但是 目前尚无可用于增强 DS 患者认知功能的治疗方法。 旨在使用重组人粒细胞-巨噬细胞设计并完成成人 DS 的临床试验 集落刺激因子（GM-CSF/sargramostim），FDA 批准的一种药物，用于增加产量和 分化各种白细胞，在众多患者中拥有近 30 年的出色安全历史 在之前的一项回顾性研究中，我们发现沙格司亭治疗与认知能力相关。 骨髓化疗和造血细胞移植后白血病患者的改善。 最近结束的一项 II 期临床试验 (NCT01409915)，我们发现沙格司亭治疗三周 在轻度至中度阿尔茨海默病 (AD) 参与者中是安全且耐受性良好的，并且与 MMSE 改善，神经退行性变生物标志物（Tau 和 UCH-L1）减少，但没有证据表明 此外，我们发现用小鼠 GM-CSF 治疗可改善认知能力和 改善 DS 小鼠模型（没有 AD 病理学）的星形胶质细胞增生，迅速逆转认知能力 损伤并消除 AD 小鼠模型中的一些脑淀粉样蛋白病理，并且它可以改善年龄 许多其他研究表明，GM-CSF 与老年野生型小鼠的认知能力下降有关。 具有神经保护、抗凋亡、神经源性作用，对多种神经系统疾病和损伤有益 例如，在帕金森病受试者和中风、脊髓损伤动物模型中的临床试验中， 具体来说，该提案旨在调查是否可以治疗创伤性脑损伤。 FDA推荐剂量的沙格莫司亭对于患有DS的成人是安全且可耐受的，是否可以改善 认知功能、生活质量和日常生活活动的测量，以及是否可以降低 Tau 和 我们已证明血液中的 UCH-L1 生物标志物可证明神经炎症和神经变性 患有 DS 的人以及 AD 患者中通过 GM-CSF 治疗可以减少。