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Multiplexed nanoparticle delivery to increase CRISPR/Cas gene editing for enhanced cancer therapy

多重纳米颗粒递送可增强 CRISPR/Cas 基因编辑，从而增强癌症治疗

基本信息

批准号：
10419618
负责人：
Daniel John Siegwart
金额：
$ 39.17万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10419618
关键词：
Affect Antibodies Applications Grants Biological Markers Brain Cancer Model Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coupled Data Encapsulated Endocytosis Exhibits Extracellular Matrix Focal Adhesion Kinase 1 Formulation Future Gene Silencing Genes Genetic Enhancement Genetic Suppression Genetically Engineered Mouse Growth Immune Infiltration Intravenous Kinetics Lipids Liver Lung Malignant Neoplasms Malignant neoplasm of liver Measures Mechanics Mediating Messenger RNA Modeling Modification Mus Muscle Non-Small-Cell Lung Carcinoma Nucleic Acids Organ Outcome Pathway interactions Penetration Primary carcinoma of the liver cells Proteins Series Small Interfering RNA Solid Neoplasm Spleen System Therapeutic Tissues Toxic effect Treatment Efficacy Tropism Tumor Burden Tumor Expansion Tumor Tissue Work base cancer immunotherapy cancer therapy design gene correction gene repair genome editing improved in vivo innovation knock-down lipid nanoparticle lung cancer cell mRNA delivery mechanical force mechanical properties nanoparticle nanoparticle delivery neoplastic cell nucleic acid delivery programmed cell death ligand 1 programs repaired therapeutic genome editing three dimensional cell culture tumor tumor microenvironment tumor progression uptake

项目摘要

Project Summary The programmable CRISPR/Cas gene editing system has great potential for cancer treatment due to the ability to precisely inactivate or repair cancer-related genes. However, delivery of CRISPR to solid tumors for efficient cancer therapy remains limited by the uniquely stiff and fibrotic tumor microenvironment that acts as a barrier to nanoparticle uptake. Here, we propose to directly target tumor tissue mechanics via a multiplexed lipid nanoparticle (LNP) approach involving co-delivery of focal adhesion kinase (FAK) siRNA, Cas9 mRNA, and sgRNA (siFAK + CRISPR LNPs) to enable tumor delivery and enhance gene editing efficacy. We will leverage our recently developed non-viral Selective ORgan Targeting (SORT) LNP platform that enables tissue-specific nucleic acid delivery, protein delivery, and genome editing following intravenous (IV) administration. The proposed approach involves a unique combination of siRNA-mediated gene silencing of FAK, a key modulator of tumor ECM, and CRISPR-mediated gene editing (deletion) of tumor-related genes via a single all-in-one nanoparticle approach. We will further leverage Liver and Lung SORT LNPs for to evaluate gene editing as a strategy for permanent inactivation of programmed death-ligand 1 (PD-L1), supported by the clinical limitations of anti-PD-L1 antibody atezolizumab therapy in hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC). In this grant proposal, we Aim to (1) establish how FAK knockdown enhances SORT LNP-mediated mRNA delivery and CRISPR gene editing, (2) optimize Liver and Lung SORT LNP formulations for multiplexed siRNA + Cas9 mRNA + sgRNA delivery, and (3) evaluate the therapeutic efficacy of Liver and Lung SORT siFAK + Cas9 mRNA + sgPD-L1 delivery in orthotopic and genetically engineered mouse models of cancer. Regulating the mechanical properties of tumor cells/ECM for enhancing the genetic suppression in tumor tissues provides an innovative strategy for treating cancer using CRISPR. We anticipate that this general approach could further synergize with additional types of therapeutics in the future.

项目总结