Novel Systemic Delivery of Peptide-Mediated Anti-Sense Oligonucleotides for Dementia with Lewy Bodies

肽介导的反义寡核苷酸的新型全身递送治疗路易体痴呆

• 批准号: 10186335
• 负责人: Robert A Rissman
• 金额: $ 175.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186335
• 关键词: Address; Affect; Affinity; Age-Months; Alzheimer' s Disease; Amino Acids; Amyloid beta-Protein; Antisense Oligonucleotides; Astrocytes; Autopsy; Behavioral; Binding; Blood - brain barrier anatomy; Brain; Cells; Clinical Trials; Collaborations; Consultations; Data; Dementia; Dementia with Lewy Bodies; Disease; Dose; Drug Kinetics; Endothelium; FYN gene; Half-Life; Human; Impaired cognition; Induced pluripotent stem cell derived neurons; Injections; Intrathecal Injections; Kinetics; Learning; Lewy Bodies; Lewy neurites; MAPT gene; Measures; Mediating; Memory; Messenger RNA; Metabolic Clearance Rate; Methodology; Methods; Modeling; Motor; Motor Activity; Multiple System Atrophy; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Oligonucleotides; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Patients; Peptide Transport; Peptides; Peripheral; Plasma; Proteins; RNA; Recovery; Regulation; Ribonucleotides; Role; Safety; Small Interfering RNA; Synapses; Therapeutic; Tissues; Toxicology; Translations; Treatment Efficacy; Vertebral column; Work; abeta accumulation; aging population; alpha synuclein; base; behavior test; clinical efficacy; cognitive ability; cognitive testing; design; efficacy testing; experimental study; human model; improved; in vitro Model; induced pluripotent stem cell; intraperitoneal; knock-down; motor symptom; mouse model; nervous system disorder; neuroinflammation; neuronal survival; neuropathology; novel; novel strategies; pharmacokinetics and pharmacodynamics; prevent; protein aggregation; protein expression; tau Proteins; tau aggregation; uptake

PROJECT SUMMARY/ABSTRACT Neurodegenerative disorders of the aging population are characterized by the progressive accumulation of proteins such as α-synuclein (α-syn), amyloid beta (Aß) and microtubule associate protein (tau). Misfolded and aggregated α-syn has been implicated in neurological disorders with Parkinsonism including Dementia with Lewy Body, Parkinson’s disease (PD), and Multiple Systems Atrophy. Accumulation of α-syn has even been confirmed in over 50% of Alzheimer’s disease (AD). Recent evidence points to a role of α-syn accumulation in the aggregation of tau and Aß in AD. Thus, regulation of α-syn expression may be crucial to the therapeutic control of numerous neurodegenerative diseases. Short interfering RNA molecules (siRNA) can bind specifically to target RNAs and deliver them for degradation; however, RNA molecules do not cross the blood- brain barrier so the only method for delivery is repeat intra-thecal injections. We recently developed a peptide (ApoB11) that binds oligonucleotides for transport across the blood-brain barrier following systemic administration. Using this peptide, we showed that we can deliver a si α-syn to reduce expression of α- synuclein in a mouse. We recently converted the ribonucleotide backbone of this siRNA to a 2’-MOe anti-sense oligonucleotide to increase half-life and affinity to the mRNA target. We plan to examine the pharmacokinetics and toxicology of systemic ApoB11:2’-MOe si α-syn following intra-peritoneal delivery in an α-syn tg mouse model of DLB. Then we will examine the ability of the ApoB11:2’-MOe si α-syn to reduce α-syn and improve survival of neurons and improve cognitive ability and motor coordination in an α-syn tg mouse model of DLB. Finally, we will examine the ability of the ApoB11:2’-MOe si α-syn to reduce the accumulation of α-syn in an in vitro model of human DLB neurons derived from iPSC cells in a blood-brain barrier model. We believe this may represent a new method of therapeutic delivery for DLB and other neurological disorders.

项目摘要/摘要 老年人群的神经退行性疾病的特点是进行性积累 α-突触核蛋白(α-syn)、淀粉样β蛋白(A？)和微管相关蛋白(Tau)等蛋白质。折叠错误和 聚集的α-SYN与帕金森氏症的神经障碍有关，包括痴呆 路易体、帕金森氏病(PD)和多系统萎缩。α-SYN的积累甚至已经被 在超过50%的阿尔茨海默病(AD)中得到证实。最近的证据表明，α-SYN积累在 公元中tau和A？的聚集。因此，调节α-SYN的表达可能对治疗 控制多种神经退行性疾病。短干扰RNA分子(SiRNA)可以结合 专门针对RNA并将其传递给降解；然而，RNA分子不会穿过血液- 脑屏障，所以唯一的给药方法是重复鞘内注射。我们最近开发了一种多肽 (ApoB11)结合寡核苷酸，以便在系统性疾病后通过血脑屏障运输 行政管理。利用该肽，我们发现我们可以传递一个siα-syn来降低α-的表达。 小鼠体内的突触核蛋白。我们最近将这种siRNA的核糖核苷酸骨架转化为2‘-moe反义 寡核苷酸以增加半衰期和与信使核糖核酸靶标的亲和力。我们计划检查药物动力学 系统性载脂蛋白B11：2‘-MoE siα-syn对α-syn转基因小鼠腹腔注射的毒理学研究 DLB的模型。然后，我们将检查载脂蛋白B11：2‘-Moe siα-syn降低α-syn并提高其性能的能力 在α-SYN TG小鼠模型中，神经元存活并改善认知能力和运动协调性。 最后，我们将研究载脂蛋白B11：2‘-Moe siα-syn减少α-syn在IN中积累的能力 血脑屏障模型中IPSC细胞来源的人DLB神经元的体外模型。我们相信这可能会 代表了一种治疗DLB和其他神经疾病的新方法。