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 衰老人群的神经退行性疾病的特征是 蛋白质，例如α-突触核蛋白（α-syn），淀粉样蛋白β（Aß）和微管缔合蛋白（TAU）。 聚集的α-SYN与帕金森氏症的神经学疾病有关，包括与痴呆有关。 Lewy身体，帕金森氏病（PD）和多个系统的萎缩。 在阿尔茨海默氏病（AD）中确认超过50％。 tau和aß的聚集在AD中。 控制众多神经退行性疾病。 专门针对RNA并将其递送降解； 脑屏障因此，唯一的输送方法是重复进行注射。 （APOB11）结合寡核苷酸，用于全身后横穿血脑屏障的传输 使用此肽，我们表明我们可以提供Siα-Syn 小鼠中的突触核蛋白。 寡核苷酸增加半衰期和对mRNA靶标的亲和力。 全身性apob11的毒理学：2'-moesiα-syn-syn folla-peritoneal delitoneal递送在α-syn Tg小鼠中 然后，DLB的模型将检查APOB11：2'-MOESIα-Syn以减少α-Syn 神经元的存活并提高DLBα-Syn TG鼠标中的认知能力和运动配位。 最后，我们将研究APOB11：2'-MOE SI SYN的能力，以减少In In In In In In In In In In In In In In In In in。 人类DLB神经元的体外模型是从iPSC细胞中衍生的，我们认为这可能是5月份。 代表了DLB和其他神经系统疾病的一种新方法。