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:
    10263159
  • 负责人:
  • 金额:
    $ 78.28万
  • 依托单位:
  • 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 2022-07-31
  • 项目状态:
    已结题

项目摘要

CRISPR-based gene editing of the brain has the potential to revolutionize the treatment of neurological diseases. A large number of incurable brain diseases, such as Huntington's, Alzheimer's and Parkinson's disease, are caused by the over-expression of pathogenic proteins and could be treated with CRISPR based therapeutics. However, despite its potential, developing CRISPR based therapeutics for the brain has been challenging because of delivery problems. In particular, two key challenges need to be solved before gene editing in the brains of large animals and in humans is possible. First, strategies for efficiently and safely delivering Cas9 and gRNA into neurons, after an intracranial injection, need to be developed. Second, strategies that can enable a large volume of brain tissue (> 1 cm) to be transfected after an intracranial injection of CRISPR reagents also need to be developed. The central objective of this proposal is to develop a delivery strategy for gene editing the brains of large animals after an intracranial injection, termed convection-enhanced CRISPR (C-CRISPR). C-CRISPR is based on using convection-enhanced delivery (CED) to deliver an engineered Cas9 RNP, which has been fused to multiple nuclear localization signals (NLS), and has been encapsulated in PEGylated block copolymers. C-CRISPR addresses the key translational bottlenecks that have prevented CRISPR from having a translational impact in the brain. In particular, because it delivers the Cas9 RNP directly, it avoids the toxicity problems of viruses and the manufacturing challenges of using mRNA, and consequently has great translational potential. In addition, C-CRISPR uses CED to distribute the Cas9 RNP across centimeters of brain tissue, and therefore has the potential to edit the brains of large animals. C-CRISPR is based on our preliminary data demonstrating that the Cas9 RNP fused to multiple NLS signals can edit genes in murine brains after an intracranial injection, and that Cas9 RNP complexed to PEG-block copolymers can be delivered to centimeters of brain tissue, in the striatum, after delivery via CED. CED of engineered Cas9 RNP complexed to PEG block copolymers, therefore, has the potential to edit genes in human patients. We propose therefore the following aims/milestones: UG3 Specific Aim 1. Develop C-CRISPR formulations that distribute throughout the striatum of rats UG3 Specific Aim 2. Develop C-CRISPR formulations that edit centimeters of brain tissue UH3 Specific Aim 1. Develop C-CRISPR formulations that edit centimeters of tissue in pig brains The experiments in this proposal are significant because, if successful, C-CRISPR will be the first example of a non-viral delivery strategy that can edit genes in the brains of large animals. The experiments in this proposal are innovative because C-CRISPR is the first example of a delivery strategy that effectively integrates 3 complementary technologies, (1) engineered Cas9 RNPs (2) PEGylation and (3) convective enhanced diffusion, and will provide a roadmap for developing strategies for gene editing in higher animals.
基于crispr的大脑基因编辑有可能彻底改变神经系统疾病的治疗。

项目成果

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会议论文数量(0)
专利数量(0)

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Krystof S Bankiewicz其他文献

Krystof S Bankiewicz的其他文献

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{{ truncateString('Krystof S Bankiewicz', 18)}}的其他基金

Validation of a single-pass surgical trajectory to enable AAV2-hAADC infusion into brainstem and mid-brain in nonhuman primate
验证单次手术轨迹,使 AAV2-hAADC 能够输注到非人灵长类动物的脑干和中脑
  • 批准号:
    10040048
  • 财政年份:
    2020
  • 资助金额:
    $ 78.28万
  • 项目类别:
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
  • 批准号:
    10012948
  • 财政年份:
    2019
  • 资助金额:
    $ 78.28万
  • 项目类别:
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
  • 批准号:
    9810326
  • 财政年份:
    2019
  • 资助金额:
    $ 78.28万
  • 项目类别:
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
  • 批准号:
    10669525
  • 财政年份:
    2019
  • 资助金额:
    $ 78.28万
  • 项目类别:
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
  • 批准号:
    10619048
  • 财政年份:
    2019
  • 资助金额:
    $ 78.28万
  • 项目类别:
A Safety and Efficacy Study of AAV2-hAADC for AADC Deficiency
AAV2-hAADC 治疗 AADC 缺乏症的安全性和有效性研究
  • 批准号:
    10505606
  • 财政年份:
    2016
  • 资助金额:
    $ 78.28万
  • 项目类别:
A Safety and Efficacy study of AAV2-hAADC for AADC deficiency
AAV2-hAADC 治疗 AADC 缺乏症的安全性和有效性研究
  • 批准号:
    10299327
  • 财政年份:
    2016
  • 资助金额:
    $ 78.28万
  • 项目类别:
Translational AAV Delivery Platform to the Brain
大脑转化 AAV 传递平台
  • 批准号:
    8513428
  • 财政年份:
    2011
  • 资助金额:
    $ 78.28万
  • 项目类别:
Translational AAV Delivery Platform to the Brain
大脑转化 AAV 传递平台
  • 批准号:
    8696895
  • 财政年份:
    2011
  • 资助金额:
    $ 78.28万
  • 项目类别:
Translational AAV Delivery Platform to the Brain
大脑转化 AAV 传递平台
  • 批准号:
    8084288
  • 财政年份:
    2011
  • 资助金额:
    $ 78.28万
  • 项目类别:

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