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）：唐氏综合征（DS）或第21三体性是由21染色体的一式字母引起的。该染色体编码包括淀粉样蛋白蛋白前体（APP）在内的许多基因，该基因表达了β-淀粉样蛋白（Aβ）。因此，这会导致Aβ的过量产生。几乎所有受DS影响的人都显示出与40岁的Aβ相关的神经病理学变化。尸检时DS患者发现的淀粉样蛋白斑块与非DS人群中阿尔茨海默氏病的个体中发现的淀粉样板相同。因此，患有DS的人无疑代表可预测的AD病例。这就提出了一个问题，即患有DS的人是否可以从持续发展疾病的疾病中受益，从而改变偶然的AD抗淀粉样蛋白干预措施。反过来，提供了针对普通人群零星广告的这种干预措施的效率和时机的重要见解。 ACI-24是一种疫苗，该疫苗由锚定在脂质体中的棕榈酰化的Aβ肽组成，并与单磷酸脂质A（MPLA）调节混合。 ACI-24诱导对Aβ的抗体，从而降低固体Aβ。此外，ACI-24诱导了一项抗Aβ抗体反应，该抗体反应主要独立于T细胞激活，因此，预计作为概念验证研究，TS65DN小鼠已被ACI-DS-01免疫（Murine等于ACI-24），并具有稳健的抗体响应，并且在抗体的响应中，TS65DN小鼠已被免疫。这项工作证明了ACI-24作为抗Aβ疫苗对Ds认知下降的有益作用。临床前安全数据以及AD中的I/II期临床试验均表明ACI-24具有良好的安全性。建议研究将在I期临床试验中研究ACI-24疫苗的安全性，耐受性以及35-55岁成人的免疫原性。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免疫疗法，以治疗唐氏综合症的阿尔茨海默氏病。