ACTIVE IMMUNOTHERAPY FOR COGNITIVE DECLINE IN ADULTS WITH DOWN SYNDROME

描述（由申请人提供）：唐氏综合症（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，包括表达β-淀粉样蛋白（Aβ）的淀粉样蛋白前体（APP）。因此，这导致过量生产的Aβ。几乎所有患有退行性痴呆的人在40岁时都表现出与Aβ相关的神经病理改变。在尸检中发现的淀粉样斑块在患有退行性痴呆的个体中与在非退行性痴呆人群中阿尔茨海默病患者中发现的相同。因此，患有退行性痴呆的人无疑代表着可预见的AD病例。这就提出了一个问题，即对于散发性阿尔茨海默病，DS患者是否可以从正在进行的开发疾病修饰抗淀粉样蛋白干预措施中获益。并且，反过来，为针对普通人群中散发性阿尔茨海默病的干预措施的有效性和时机提供了重要的见解。ACI-24是一种由锚定在脂质体中的棕榈酰化a β肽组成的疫苗，并与单磷酰脂质a （MPLA）佐剂混合。ACI-24诱导抗Aβ抗体，从而降低可溶性Aβ。此外，ACI-24诱导的抗a β抗体反应在很大程度上独立于T细胞活化，因此有望发挥良好的安全性。作为一项概念验证研究，用ACI-DS-01 （ACI-24的小鼠等量物）免疫Ts65Dn小鼠，观察到强大的抗体反应和记忆能力的改善。这项工作已经证明了ACI-24作为抗a β疫苗治疗退行性痴呆的认知能力下降的有益作用。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。拟议的研究将在一项针对35-55岁成年DS患者的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。该项目将测试首个用于治疗唐氏综合症患者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.