ACTIVE IMMUNOTHERAPY FOR COGNITIVE DECLINE IN ADULTS WITH DOWN SYNDROME

描述(申请人提供)：唐氏综合症(DS)，或21三体，由21号染色体的三倍体引起。该染色体编码许多基因，包括表达β-淀粉样蛋白(A-β)的淀粉样蛋白前体(APP)。因此，这导致了Aβ的过量生产。几乎所有受DS影响的人在40岁之前都会出现与Aβ相关的神经病理变化。在DS患者尸检中发现的淀粉样斑块与在非DS人群中发现的阿尔茨海默病患者的淀粉样斑块相同。因此，患有DS的人无疑代表了可预见的AD病例。这提出了一个问题，即DS患者是否可以从为散发性AD开发疾病修改抗淀粉样蛋白干预措施的持续努力中受益。并反过来为针对普通人群中的散发性AD的此类干预的有效性和时机提供了重要的见解。ACI-24是一种疫苗，由固定在脂质体中的棕榈酰化Aβ多肽与单磷酰脂A佐剂混合而成。ACI-24可诱导抗Aβ抗体，从而降低可溶性Aβ。此外，ACI-24诱导的抗Aβ抗体反应在很大程度上不依赖于T细胞的激活，因此有望发挥良好的安全性。作为一项概念验证研究，ACI-DS-01(相当于ACI-24的小鼠)已免疫Ts65Dn小鼠，并观察到强劲的抗体反应和记忆能力的改善。这项工作证明了ACI-24作为抗A-β疫苗治疗DS认知功能减退的有益效果。临床前安全性数据以及正在进行的AD的I/II期临床试验表明，ACI-24具有良好的安全性。这项拟议的研究将在35-55岁的DS成年人的I期临床试验中调查ACI-24疫苗的安全性、耐受性和免疫原性。对认知功能和AD生物标志物的影响将是次要终点。该项目将测试第一种治疗唐氏综合征阿尔茨海默病的免疫疗法。

DESCRIPTION (provided by APPLICANT): Down syndrome (DS), or trisomy 21, is caused by a triplication of chromosome 21. This chromosome encodes many genes including amyloid protein precursor (APP), which expresses β-Amyloid (Aβ). Consequently, this results in excess production of Aβ. Virtually all people affected with DS show the neuropathological changes related to Aβ by age 40. The amyloid plaques found at autopsy in individuals with DS is identical to those found in individuals with Alzheimer's disease in the non-DS population. Therefore people with DS doubtlessly represent predictable AD cases. This raises the question as to whether individuals with DS could benefit from ongoing efforts to develop disease modifying anti- amyloid interventions for sporadic AD. And, in turn, provide important insights about the efficacy and timing of such interventions targeting sporadic AD in the general population. ACI-24 is a vaccine composed of a palmitoylated Aβ peptide anchored in liposomes and mixed with the monophosphoryl lipid A (MPLA) adjuvant. ACI-24 induces antibodies against Aβ and thereby lowers soluble Aβ. In addition, ACI-24 induces an anti-Aβ antibody response that is largely independent from T- cell activation and, therefore, is expected to exert a favorable safety profile As a proof-of-concept study, Ts65Dn mice have been immunized with ACI-DS-01 (murine equivalent of ACI-24), and a robust antibody response and an improvement in memory capacity has been observed. This work has demonstrated the beneficial effect of ACI-24 as anti-Aβ vaccine for the treatment of cognitive decline in DS. The preclinical safety data as well as the ongoing Phase I/II clinical trial in AD indicate a favorable safety profile for ACI-24. The propose study will investigate the safety, tolerability, as well as immunogenicity of the ACI-24 vaccine in a Phase I clinical trial in adults with DS aged 35-55. Effects on cognitive function and AD biomarkers will be secondary endpoints. This project will be testing the first immunotherapy for the treatment of Alzheimer's disease in Down syndrome.