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

项目总结/摘要 唐氏综合症患者的额叶、海马和小脑发育不全 以及轻度到重度的智力残疾，这对他们独立运作的能力提出了挑战。任何 认知能力的提高将大大改善他们的生活质量和日常生活能力， 目前还没有可用于增强DS患者认知功能的治疗剂。这项建议 旨在设计并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/沙格司亭），FDA批准的药物，用于增加生产和 分化各种白色血细胞，在许多患者中具有近30年的良好安全性历史 人口。在以前的一项回顾性研究中，我们发现沙格司亭治疗与认知功能相关， 白血病患者在骨髓化学消融和造血细胞移植后的改善。在 最近结束的II期临床试验（NCT 01409915），我们发现三周的沙格司亭治疗 在轻度至中度阿尔茨海默病（AD）参与者中安全且耐受性良好， MMSE改善，神经变性生物标志物（Tau和UCH-L1）减少，但没有证据表明 淀粉样蛋白减少。此外，我们发现用鼠GM-CSF治疗可改善认知， 改善DS小鼠模型（无AD病理）中的星形胶质细胞增生， 在AD小鼠模型中，它可以减少和消除一些脑淀粉样病变，并且它可以改善年龄- 老年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、抗凋亡、神经原性，并且有益于多种神经疾病和损伤， 例如，在帕金森病受试者的临床试验中，以及在中风，脊髓损伤， 和创伤性脑损伤具体来说，这项建议旨在调查是否治疗与 FDA推荐剂量的沙格司亭在DS成人患者中是安全和耐受的，无论它是否能改善 认知功能、生活质量和日常生活活动的指标，以及它是否能降低Tau和 血液中的UCH-L1生物标志物，我们已经证明了神经炎症和神经变性的证据， DS患者和AD患者通过GM-CSF治疗可以减少。

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.