A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies
A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies
复制标题
DOI：
10.1093/brain/aww036
复制
发表时间：
2016-05-01
期刊：
影响因子：
14.5
通讯作者：
Aebischer, Patrick
中科院分区：
文献类型：
--
作者：
Lathuiliere, Aurelien;Laversenne, Vanessa;Aebischer, Patrick
针对有毒错误折叠蛋白的被动免疫可以提供对神经退行性疾病的保护。LahuiliSre等人的研究。报道了一种可回收设备的开发，用于包裹分泌重组抗淀粉样β抗体的细胞。当被植入阿尔茨海默病小鼠模型中时，该系统向大脑传递抗体，并减少淀粉样蛋白和tau病理。针对有毒错误折叠的蛋白质的被动免疫可以提供对神经退行性疾病的保护。LahuiliSre等人的研究。报道了一种可回收设备的开发，用于包裹分泌重组抗淀粉样β抗体的细胞。当被植入阿尔茨海默病小鼠模型中时，该系统将抗体传递到大脑，并减少淀粉样蛋白和tau病理。针对错误折叠的有毒蛋白的被动免疫是治疗神经退行性疾病的一种有前途的方法。为了有效地治疗阿尔茨海默病，最近的临床数据表明，针对淀粉样β蛋白的单抗应该在与不可逆脑损伤相关的症状出现之前注射。因此，开发适用于疾病预防的持续抗体传递技术至关重要。在这里，我们使用生物活性细胞植入物在皮下组织中传递重组抗淀粉样β抗体来解决这个问题。一种可渗透到大分子的胶囊装置支持免疫活性异基因受者肌源性细胞长达10个月以上的存活。这些被包裹的细胞经过基因工程，可以分泌高水平的抗淀粉样β抗体。外周植入导致持续的抗体输送，达到血浆水平超过50A微克/毫升。在一项概念验证研究中，我们证明了由该系统产生的重组抗体穿透大脑并在两个阿尔茨海默氏病小鼠模型中结合淀粉样斑块。当被包裹的细胞在TauPS2APP小鼠的淀粉样斑块沉积开始之前被植入时，长期暴露于抗淀粉样β抗体可显著降低大脑中淀粉样β蛋白(40)和淀粉样β蛋白(42)的水平，减少淀粉样斑块的负担，最显著的是，防止海马区的磷酸-tau病理。这些结果支持使用包裹细胞植入物进行被动免疫治疗，以对抗错误折叠的蛋白质，这些蛋白质积累在阿尔茨海默病和其他神经退行性疾病中。
Passive immunization against toxic misfolded proteins could offer protection against neurodegenerative disease. LathuiliSre et al. report the development of a retrievable device to encapsulate cells secreting recombinant anti-amyloid-beta antibodies. When implanted in mouse models of Alzheimer's disease, the system delivers antibodies to the brain and reduces amyloid and tau pathologies.Passive immunization against toxic misfolded proteins could offer protection against neurodegenerative disease. LathuiliSre et al. report the development of a retrievable device to encapsulate cells secreting recombinant anti-amyloid-beta antibodies. When implanted in mouse models of Alzheimer's disease, the system delivers antibodies to the brain and reduces amyloid and tau pathologies.Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-beta peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-beta antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-beta antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 A mu g/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-beta antibodies dramatically reduces amyloid-beta(40) and amyloid-beta(42) levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.