Genome Editing the Blood-Brain Barrier with Sonoselective Focused Ultrasound

利用声选择性聚焦超声对血脑屏障进行基因组编辑

基本信息

  • 批准号:
    10554403
  • 负责人:
  • 金额:
    $ 59.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-05-15 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

The endothelium of the cerebral microcirculation is a critical component of the blood-brain barrier (BBB), which protects neural tissue through the presence of tight junctions between endothelial cells and efflux transporters that extrude many compounds back into the bloodstream. When developing drug delivery strategies for brain pathologies, these efflux transporters [e.g. multi drug resistance 1 (MDR1)] present a considerable challenge to effective drug delivery, as they limit the exposure of central nervous system (CNS) pathologies to many systemically administered agents. Meanwhile, nutrient transporters [e.g. glucose transporter 1 (GLUT1)] are critical for maintaining normal brain function. Indeed, genetic mutation(s) of GLUT1 can cause recurrent epileptic seizures, microcephaly, intellectual disability, spasticity, ataxia, and dysarthria. Given this central role in health and disease in the brain, the endothelium of the BBB represents a rich target for therapeutic genomic manipulation. In this proposal, we will engineer a platform technology capable of genome editing the BBB in a safe, endothelial cell-selective, and non-invasive manner, with precise loco-regional targeting provided by MR image-guidance. We call this approach, wherein very low pressure focused ultrasound is used to activate plasmid-coated microbubbles, “sonoselective” gene delivery. This is because, instead of employing a cell-specific promoter, ultrasound (i.e. “sono”) alone “selects” which cell type is transfected. Since endothelial cell-specific promoters are unnecessary, a vast array of genetic manipulations may be employed. In Aim 1, we will engineer acoustically-activated delivery agents that sonoselectively edit the genome of blood-brain barrier endothelium. This will entail testing CRISPR-Cas9 “nickase” plasmids with varying guide RNA (gRNA) pair sequences for their ability to sonoselectively delete GLUT1 and MDR1 from BBB endothelium. We will also test whether efficiency can be improved by incorporating plasmids into non-viral polymer nanoparticles (NPs) that are coupled covalently to MBs with non-immunogenic linkers. The most promising compositions will then be examined functionally using positron emission tomography (PET) [i.e. 18F-FDG for brain metabolism changes after GLUT1 deletion and (R)-[11C]verapamil for drug efflux changes after MDR1a deletion]. Further, single cell RNA sequencing (scRNAseq) will be used to assess the cell selectivity and efficacy of gene deletion. In Aim 2, we will augment the efficiency and control of sonoselective genome editing by rationally manipulating focused ultrasound parameters. We will test whether increasing FUS burst duration improves plasmid delivery and subsequent gene (GLUT1 and MDR1) deletion efficiency. We will also test whether we can control sonoselective genome editing using a feedback control system based on acoustic emissions. Once completed, we will have established a safe, non-invasive, MR image-guided, platform for genome editing of endothelium in the BBB. We submit that such an approach will have multiple applications in pre-clinical neuroscience research and considerable potential as a therapeutic approach to treating many diseases of the CNS.
脑微循环的内皮是血脑屏障(BBB)的重要组成部分。

项目成果

期刊论文数量(0)
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Richard J. Price其他文献

A novel ‘bottom-up’ synthesis of few- and multi-layer graphene platelets with partial oxidation via cavitation
  • DOI:
    10.1016/j.ultsonch.2019.03.020
  • 发表时间:
    2019-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Richard J. Price;Paul I. Ladislaus;Graham C. Smith;Trevor J. Davies
  • 通讯作者:
    Trevor J. Davies
Dynamics of Adult Axin2 Cell Lineage Integration in Granule Neurons of the Dentate Gyrus
齿状回颗粒神经元中成人 Axin2 细胞谱系整合的动态
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Khadijeh A. Sharifi;Faraz Farzad;Sauson Soldozy;Richard J. Price;M. Y. S. Kalani;P. Tvrdik
  • 通讯作者:
    P. Tvrdik
Focused ultrasound augments the delivery and penetration of model therapeutics into cerebral cavernous malformations
聚焦超声增强了模型治疗药物向脑海绵状血管畸形的递送和渗透。
  • DOI:
    10.1016/j.jconrel.2025.113861
  • 发表时间:
    2025-07-10
  • 期刊:
  • 影响因子:
    11.500
  • 作者:
    Delaney G. Fisher;Matthew R. Hoch;Catherine M. Gorick;Claire Huchthausen;Victoria R. Breza;Khadijeh A. Sharifi;Petr Tvrdik;G. Wilson Miller;Richard J. Price
  • 通讯作者:
    Richard J. Price
Focused ultrasound-microbubble treatment arrests the growth and formation of cerebral cavernous malformations
聚焦超声微泡治疗可阻止脑海绵状畸形的生长和形成
  • DOI:
    10.1038/s41551-025-01390-z
  • 发表时间:
    2025-05-13
  • 期刊:
  • 影响因子:
    26.600
  • 作者:
    Delaney G. Fisher;Tanya Cruz;Matthew R. Hoch;Khadijeh A. Sharifi;Ishaan M. Shah;Catherine M. Gorick;Victoria R. Breza;Anna C. Debski;Joshua D. Samuels;Jason P. Sheehan;David Schlesinger;David Moore;James W. Mandell;John R. Lukens;G. Wilson Miller;Petr Tvrdik;Richard J. Price
  • 通讯作者:
    Richard J. Price

Richard J. Price的其他文献

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{{ truncateString('Richard J. Price', 18)}}的其他基金

Genome Editing the Blood-Brain Barrier with Sonoselective Focused Ultrasound
利用声选择性聚焦超声对血脑屏障进行基因组编辑
  • 批准号:
    10403487
  • 财政年份:
    2021
  • 资助金额:
    $ 59.35万
  • 项目类别:
ImmunoPET Assessment of anti-CD47 Immunotherapy Delivery to Glioblastoma with Focused Ultrasound
使用聚焦超声对胶质母细胞瘤进行抗 CD47 免疫治疗的免疫PET评估
  • 批准号:
    10041000
  • 财政年份:
    2020
  • 资助金额:
    $ 59.35万
  • 项目类别:
Innovative systemic gene therapy for treating Parkinson's disease
治疗帕金森病的创新系统基因疗法
  • 批准号:
    10164880
  • 财政年份:
    2019
  • 资助金额:
    $ 59.35万
  • 项目类别:
Innovative systemic gene therapy for treating Parkinson's disease
治疗帕金森病的创新系统基因疗法
  • 批准号:
    9927696
  • 财政年份:
    2019
  • 资助金额:
    $ 59.35万
  • 项目类别:
Innovative systemic gene therapy for treating Parkinson's disease
治疗帕金森病的创新系统基因疗法
  • 批准号:
    10394379
  • 财政年份:
    2019
  • 资助金额:
    $ 59.35万
  • 项目类别:
Innovative systemic gene therapy for treating Parkinson's disease
治疗帕金森病的创新系统基因疗法
  • 批准号:
    10609832
  • 财政年份:
    2019
  • 资助金额:
    $ 59.35万
  • 项目类别:
Endothelial DNA Methylation, Arteriogenic Capacity, and Shear Stress "Set-Point."
内皮 DNA 甲基化、动脉生成能力和剪切应力“设定点”。
  • 批准号:
    9311466
  • 财政年份:
    2017
  • 资助金额:
    $ 59.35万
  • 项目类别:
Application of Laser Speckle Flowmetry to Vascular Remodeling
激光散斑流量计在血管重塑中的应用
  • 批准号:
    8887112
  • 财政年份:
    2014
  • 资助金额:
    $ 59.35万
  • 项目类别:
Application of Laser Speckle Flowmetry to Vascular Remodeling
激光散斑流量计在血管重塑中的应用
  • 批准号:
    8765491
  • 财政年份:
    2014
  • 资助金额:
    $ 59.35万
  • 项目类别:
Bevacizumab Delivery to Glioblastoma with MR-Guided Focused Ultrasound
通过 MR 引导聚焦超声将贝伐珠单抗递送至胶质母细胞瘤
  • 批准号:
    8628120
  • 财政年份:
    2013
  • 资助金额:
    $ 59.35万
  • 项目类别:

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