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Development of a nanoparticle-based gene editing technology for neurological applications

开发用于神经学应用的基于纳米颗粒的基因编辑技术

基本信息

批准号：
10619048
负责人：
Krystof S Bankiewicz
金额：
$ 50万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10619048
关键词：
Alzheimer&apos s Disease Anatomy Animal Model Animals Award Biological Assay Brain Brain Diseases CRISPR therapeutics CRISPR/Cas technology California Cells Charge Clinic Clustered Regularly Interspaced Short Palindromic Repeats Complex Convection Corpus striatum structure Development Diffuse Disease Disease model Exons Formulation Genes Grant Guide RNA Human Huntington Disease Huntington gene Infusion procedures Injections Institution Knock-out Modeling Mus Neurologic Neurons Nonhomologous DNA End Joining Ohio Parkinson Disease Pathogenicity Patients Peptides Procedures Proteins Reagent Reporter Research Personnel Ribonucleoproteins Site Study models Technology Testing Thalamic structure Therapeutic Trinucleotide Repeats Universities Virus Western Blotting base behavior test brain tissue brain volume deep sequencing experimental study genome editing in vivo macromolecule mouse model mutant nanoparticle nervous system disorder novel overexpression professor rational design therapy outcome

项目摘要

Abstract This supplement proposal focuses on investigating if CRISPR Cas9 ribonucleoproteins (RNPs) complexed to cell-penetrating peptides (CPPs) can rescue mice from Huntington’s disease, using the R6/2 mouse model. These experiments are based upon our recent studies demonstrating that CPPs can efficiently transfect CRISPR Cas9-RNPs neurons in the striatum after an intracranial injection using convection enhanced delivery (CED). We have selected the 2/6 mouse model for these studies because this model has recently been rescued with Cas9 based genome editing, using AAV delivered SaCas9. In this proposal we will build on our Preliminary Studies and will inject Cas9-RNP complexed to CPPs into the striatum and thalamus, via CED, and will investigate if we can edit the huntingtin (HTT) gene to rescue mice from Huntington’s disease. If successful, these experiments will identify the levels of genome editing needed in the brain to generate therapeutic outcomes in the Huntington’s animal model.

摘要本补充提案重点研究CRISPR Cas9核糖核蛋白(RNPs)是否与在R6/2小鼠模型上，细胞穿透肽(CPPs)可以将小鼠从亨廷顿病中拯救出来。这些实验是基于我们最近的研究，证明了CPP可以有效地转染CRISPR 使用对流增强递送(CED)进行颅内注射后，纹状体中的Cas9-RNPs神经元。我们选择了2/6的小鼠模型进行这些研究，因为这个模型最近用基于Cas9的基因组编辑，使用AAV提供的SaCas9。在这份提案中，我们将在初步的基础上研究并将通过CED将与CPPS复合的Cas9-RNP注射到纹状体和丘脑，并将研究我们是否可以编辑亨廷顿蛋白(HTT)基因来拯救亨廷顿病小鼠。如果成功，这些实验将确定大脑中产生治疗结果所需的基因组编辑水平在亨廷顿的动物模型中。