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

项目总结/摘要 老年人群的神经退行性疾病的特征在于， 蛋白质如α-突触核蛋白（α-syn）、淀粉样蛋白β（AAP 10）和微管相关蛋白（tau）。错误折叠和 聚集的α-syn与帕金森综合征的神经系统疾病有关，包括痴呆症， 路易体，帕金森病（PD）和多系统萎缩。α-syn的积累甚至 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积累的作用， AD中tau蛋白和Δ β蛋白的聚集。因此，α-syn表达的调节可能是治疗性的关键。 控制多种神经退行性疾病。短干扰RNA分子（siRNA）可以结合 特异性地靶向RNA并将其递送用于降解;然而，RNA分子不穿过血液- 因此，唯一的递送方法是重复鞘内注射。我们最近开发了一种肽 ApoB 11结合寡核苷酸，用于在全身性给药后转运穿过血脑屏障 局使用这种肽，我们表明我们可以递送si α-syn以减少α-syn的表达。 突触核蛋白我们最近将该siRNA的核糖核苷酸骨架转化为2 '-莫伊反义寡核苷酸， 在一些实施方案中，所述寡核苷酸可用于增加半衰期和对mRNA靶标的亲和力。我们计划检查药物代谢动力学 在α-syn tg小鼠中腹膜内递送后全身ApoB 11：2 '-莫伊si α-syn的毒理学 DLB模型然后，我们将检查ApoB 11：2 '-莫伊si α-syn减少α-syn并改善α-syn的能力。 在DLB 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。 最后，我们将检查ApoB 11：2 '-莫伊si α-syn减少α-syn在细胞中积累的能力。 在血脑屏障模型中衍生自iPSC细胞的人DLB神经元的体外模型。我们认为这可能 代表了DLB和其他神经系统疾病的治疗递送的新方法。

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.