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

项目摘要/摘要 唐氏综合征(DS)患者额叶、海马体和小脑明显发育不良 以及轻度到严重的智力残疾，这对他们独立运作的能力构成了挑战。任何 认知能力的增强将极大地提高他们的生活质量和日常生活能力，但 目前尚无治疗方法可用于增强DS患者的认知功能。这项建议 旨在设计和完成一项使用重组人粒细胞-巨噬细胞治疗成人DS的临床试验 集落刺激因子(GM-CSF/Sargram osTim)，FDA批准的一种用于增加产量和 具有近30年优良安全性史的多种白细胞在众多患者中的分化 人口。在先前的一项回顾研究中，我们发现沙格拉司汀治疗与认知能力有关。 白血病患者骨髓化疗和造血细胞移植后的改善。在……里面 最近结束的一项II期临床试验(NCT01409915)，我们发现三周的沙雷格斯汀治疗 在轻至中度阿尔茨海默病(AD)参与者中安全且耐受性良好，并与 MMSE的改善，神经退行性变的生物标志物(Tau和UCH-L1)减少，但没有证据表明 淀粉样蛋白减少。此外，我们还发现，使用小鼠GM-CSF治疗可以改善认知和 改善DS(无AD病理)小鼠模型的星形胶质细胞增多症，使认知功能迅速逆转 损伤并消除AD模型小鼠的一些脑淀粉样病变，并延长年龄- 衰老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，抗细胞凋亡，神经源性，对几种神经疾病和损伤有益， 例如，在帕金森氏症受试者的临床试验中，在中风、脊髓损伤的动物模型中， 和创伤性脑损伤。具体地说，这项提案旨在调查是否接受了 对于患有DS的成年人，FDA推荐剂量的沙格拉司汀是安全和可耐受的，是否可以改善 测量认知功能、生活质量和日常生活能力，以及它是否可以减少Tau和Tau 血液中的UCH-L1生物标记物，我们已经证明了神经炎症和神经变性的证据 DS患者和AD患者可通过GM-CSF治疗而减少。

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.