ACTIVE IMMUNOTHERAPY FOR COGNITIVE DECLINE IN ADULTS WITH DOWN SYNDROME

描述（申请人提供）：唐氏综合征（DS），或21三体，是由21号染色体的三倍引起的。该染色体编码许多基因，包括淀粉样蛋白前体（APP），其表达β-淀粉样蛋白（Aβ）。因此，这导致Aβ的过量产生。几乎所有患有DS的人在40岁时都表现出与Aβ相关的神经病理学变化。在DS患者尸检中发现的淀粉样蛋白斑块与非DS人群中阿尔茨海默病患者的淀粉样蛋白斑块相同。因此，患有DS可疑的人代表可预测的AD病例。这就提出了一个问题，即DS患者是否可以从正在进行的开发针对散发性AD的疾病修饰性抗淀粉样蛋白干预措施的努力中获益。并且，反过来，提供了关于针对一般人群中散发性AD的此类干预措施的有效性和时机的重要见解。ACI-24是一种由棕榈酰化Aβ肽锚定在脂质体中并与单磷酰脂质A（MPLA）佐剂混合组成的疫苗。ACI-24诱导抗Aβ抗体，从而降低可溶性Aβ。此外，ACI-24诱导抗A β抗体应答，其在很大程度上独立于T细胞活化，因此预期发挥有利的安全性特征。作为概念验证研究，用ACI-DS-01（ACI-24的鼠等效物）免疫Ts 65 Dn小鼠，观察到稳健的抗体应答和记忆能力的改善。这项工作证明了ACI-24作为抗A β疫苗治疗DS认知功能下降的有益作用。临床前安全性数据以及正在进行的AD I/II期临床试验表明ACI-24具有良好的安全性特征。这项拟议的研究将在35-55岁的DS成人中进行I期临床试验，研究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用于治疗唐氏综合症中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.