ACTIVE IMMUNOTHERAPY FOR COGNITIVE DECLINE IN ADULTS WITH DOWN SYNDROME

积极免疫疗法治疗成人唐氏综合症认知能力下降

• 批准号: 8750445
• 负责人: Michael S Rafii
• 金额: $ 82.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8750445
• 关键词: Active Immunotherapy; Adjuvant; Adult; Adverse event; Affect; Age; Age-Years; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antibodies; Antibody Formation; Autopsy; Behavioral; Biochemistry; Biological; Biological Markers; Blood; Brain; Chromosomes; Chromosomes, Human, Pair 21; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Cognitive; Consensus; Controlled Clinical Trials; Data; Dementia; Development; Diagnosis; Digit structure; Disease; Dose; Double-Blind Method; Down Syndrome; Early Intervention; Europe; General Population; Genes; Goals; Hematology; Hippocampus (Brain); Immune; Immunization Schedule; Immunoglobulin G; Immunotherapeutic agent; Immunotherapy; Impaired cognition; Individual; Intervention; Learning; Liposomes; Magnetic Resonance Imaging; Measurement; Measures; Memory; Mus; Names; Neurologic Examination; Pathology; Patients; Peptides; Phase; Phase I Clinical Trials; Physical Examination; Placebo Control; Placebos; Plasma; Population; Positron-Emission Tomography; Probability; Process; Production; Randomized; Reaction Time; Research; Safety; Sampling; Semantics; Senile Plaques; Serum; Staging; Structure; T-Cell Activation; Testing; Time; Urine; Vaccination; Vaccines; Work; aged; base; classical conditioning; cognitive function; cohort; cooperative study; design; follow-up; high risk; immunogenicity; improved; inflammatory marker; insight; monophosphoryl lipid A; motor control; mouse Ts65Dn; neuropathology; neuropsychological; patient safety; preclinical safety; preclinical study; programs; public health relevance; subcutaneous; tau Proteins; tau-1

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.

描述（由申请人提供）：唐氏综合症 (DS) 或 21 三体症是由 21 号染色体三倍体引起的。该染色体编码许多基因，包括淀粉样蛋白前体 (APP)，其表达经检查的 β-淀粉样蛋白 (Aβ)。这会导致 Aβ 产生过量，几乎所有患有 DS 的人到 40 岁时都会出现与 Aβ 相关的神经病理学变化。患有 DS 的个体与非 DS 人群中患有阿尔茨海默病的个体相同，因此，患有 DS 的人无疑代表了可预测的 AD 病例，这提出了一个问题：患有 DS 的个体是否可以从持续开发疾病修饰抗药物中受益。 - 针对散发性 AD 的淀粉样蛋白干预措施，进而为针对普通人群中散发性 AD 的此类干预措施的功效和时机提供重要见解。 ACI-24 是一种由棕榈酰化 Aβ 肽组成的疫苗。脂质体并与单磷酰脂质 A (MPLA) 佐剂混合，诱导抗 Aβ 抗体，从而降低可溶性 Aβ。此外，ACI-24 诱导很大程度上独立于 T 细胞激活的抗 Aβ 抗体反应。因此，预计将发挥良好的安全性 作为一项概念验证研究，Ts65Dn 小鼠已使用 ACI-DS-01（小鼠相当于ACI-24），并且观察到了强大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 Aβ 疫苗对治疗 DS 认知能力下降的有益效果。临床前安全数据如下。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。拟议的研究将在成人 I 期临床试验中调查 ACI-24 疫苗的安全性、耐受性以及免疫原性。和DS 年龄为 35-55 岁。对认知功能和 AD 生物标志物的影响将是次要终点。该项目将测试第一个治疗唐氏综合症阿尔茨海默病的免疫疗法。