Defining the molecular interactions within nanoparticles that enable delivery of long nucleic acids

定义纳米粒子内的分子相互作用，以实现长核酸的递送

基本信息

批准号：
10365393
负责人：
Daniel John Siegwart
金额：
$ 41.97万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365393
关键词：
Affect Applications Grants Binding Biodistribution Brain COVID-19 CRISPR/Cas technology Cells Charge Chemical Structure Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Complex Coupled Dangerousness Data Development Disease Dose Dreams Drug or chemical Tissue Distribution Endothelium Epithelial Event Extrahepatic Formulation Funding Gene Delivery Genes Genetic Diseases Genetically Engineered Mouse Genomic medicine Grant Hepatocyte Human In Vitro Injections Intramuscular Intravenous Knowledge Lipids Liver Lung Measures Mediating Messenger RNA Muscle Mutate National Institute of Biomedical Imaging and Bioengineering Nucleic Acids Organ Outcome Property Proteins RNA Ribonucleoproteins Skin Specificity Spleen Structure Structure-Activity Relationship Techniques Therapeutic Uses Tissues Tropism United States National Institutes of Health Vaccines Viral Vector Work base biophysical properties cell type cellular engineering clinical translation clinically translatable efficacy validation genome editing immunogenicity improved in vivo insight lipid nanoparticle nanoparticle nanoparticle delivery novel novel therapeutics nucleic acid delivery promoter success therapeutic genome editing tool

Affect Applications Grants Binding Biodistribution Brain COVID-19 CRISPR/Cas technology Cells Charge Chemical Structure Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Complex Coupled Dangerousness Data Development Disease Dose Dreams Drug or chemical Tissue Distribution Endothelium Epithelial Event Extrahepatic Formulation Funding Gene Delivery Genes Genetic Diseases Genetically Engineered Mouse Genomic medicine Grant Hepatocyte Human In Vitro Injections Intramuscular Intravenous Knowledge Lipids Liver Lung Measures Mediating Messenger RNA Muscle Mutate National Institute of Biomedical Imaging and Bioengineering Nucleic Acids Organ Outcome Property Proteins RNA Ribonucleoproteins Skin Specificity Spleen Structure Structure-Activity Relationship Techniques Therapeutic Uses Tissues Tropism United States National Institutes of Health Vaccines Viral Vector Work base biophysical properties cell type cellular engineering clinical translation clinically translatable efficacy validation genome editing immunogenicity improved in vivo insight lipid nanoparticle nanoparticle nanoparticle delivery novel novel therapeutics nucleic acid delivery promoter success therapeutic genome editing tool

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项目摘要

Project Summary CRISPR/Cas-based gene editing has ushered in a hopeful era that dreams of new therapies for currently untreatable genetic diseases. Because mutated proteins are produced in specific cells, there is a critical need to develop organ- and cell-specific delivery strategies to realize the full potential of genomic medicines. We recently overcame this challenge through development of the first class of non-viral nanoparticles for tissue-specific genome editing. Selective ORgan Targeting (SORT) lipid nanoparticles (LNPs) enable targeted intravenous delivery of nucleic acids and proteins to the lungs, liver, and spleen, plus local delivery to the muscle, brain, and skin. Tropism is driven by inclusion of SORT molecules, which create tissue-selective 5-component SORT LNPs that are compatible with multiple gene editing techniques, including mRNA, Cas9 mRNA / sgRNA, and Cas9 ribonucleoprotein (RNP) complexes. In this grant proposal, we Aim to (1) determine the mechanism of SORT, (2) improve the efficacy and tolerability of liver-, lung-, and spleen-targeting SORT LNPs, and (3) determine the cell-specific gene editing capabilities of SORT LNPs with the potential for expanded tropism. Results will determine the fundamental mechanisms and structure-activity relationships (SAR) for non-viral nanoparticle liver, lung, and spleen tropism. This will ultimately allow targeted and safer CRISPR/Cas gene editing in vivo. We will determine these factors by adapting a unique class of LNPs, called SORT LNPs, that we developed. We will employ human cells and genetically engineered mouse models that allow quantification of precise, cell specific gene editing events. Completion of the proposed studies will (1) Elucidate the fundamental mechanisms how and why SORT LNPs target extrahepatic tissues, (2) Determine how SORT molecules control efficacy and tolerability for improved gene editing outcomes, and (3) Determine and control cell-type gene editing specificity to expand targeted gene editing. Cumulatively, this will open new avenues for CRISPR/Cas-based correction of genetic diseases by developing efficacious, safe, and clinically translatable nanoparticle carriers.

项目摘要基于CRISPR/CAS的基因编辑已经迎来了一个充满希望的时代，该时代梦见了新的疗法不可治疗的遗传疾病。因为突变的蛋白质是在特定细胞中产生的，所以很有需要制定特定于细胞和细胞的输送策略，以实现基因组药物的全部潜力。我们最近通过开发第一类非病毒纳米颗粒来克服这一挑战基因组编辑。选择性器官靶向（排序）脂质纳米颗粒（LNP）启用靶向静脉注射将核酸和蛋白质递送到肺，肝脏和脾脏，以及局部递送到肌肉，大脑和皮肤。向热力的驱动是由排序分子驱动的，这些分子会产生组织选择性的5组分排序LNP 与多种基因编辑技术兼容的技术，包括mRNA，Cas9 mRNA / sgrNA和Cas9 核糖核蛋白（RNP）复合物。在此赠款建议中，我们的目标是（1）确定排序机制，（2）提高肝，肺和脾脏靶向的LNP的功效和耐受性，（3）确定分类LNP的细胞特异性基因编辑能力，具有扩展的向流主义的潜力。结果将确定非病毒纳米颗粒的基本机制和结构活性关系（SAR）肝脏，肺和脾脏潮流。这最终将允许在体内进行针对性，更安全的CRISPR/CAS基因编辑。我们将通过调整我们开发的独特的称为Sort LNP的LNP来确定这些因素。我们将采用人类细胞和基因工程的小鼠模型，以量化精确的细胞特定的基因编辑事件。拟议研究的完成将（1）阐明基本机制（2）确定排序分子如何控制功效和改善基因编辑结果的耐受性，（3）确定并控制细胞类型基因编辑特异性扩展目标基因编辑。累积地，这将为基于CRIS/CAS的校正开放新的途径通过开发有效，安全和可翻译的纳米颗粒载体来通过遗传疾病。