Innovative systemic gene therapy for treating Parkinson's disease
治疗帕金森病的创新系统基因疗法
基本信息
- 批准号:10394379
- 负责人:
- 金额:$ 50.3万
- 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:2019-05-15 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcousticsAdhesivesAffectAnimal ModelAreaBehaviorBehavioralBiochemicalBloodBlood - brain barrier anatomyBlood CirculationBrainBrain regionCaringCellsCerebrospinal FluidClinicClinicalClinical ResearchClinical TrialsCorpus striatum structureDNADNA deliveryDataDependovirusDiseaseDisease ProgressionDisease modelDopamineDoseDrug KineticsEngineeringEnvironmentEnzymesExtracellular MatrixFeedbackFocused UltrasoundFormulationFunctional disorderGene DeliveryGene TransferGenerationsGenesGeneticGoalsHistologicHumanIn VitroInfusion proceduresInjection of therapeutic agentInjectionsJournalsKineticsLeadLettersLibrariesLocomotionMagnetic Resonance ImagingMaximum Tolerated DoseMediatingMethodsMicrobubblesModalityModelingMolecularNeurodegenerative DisordersNeurotoxinsNucleic AcidsOperative Surgical ProceduresParkinson DiseasePathologicPatientsPenetrationPersonsPharmacologyPhase I Clinical TrialsPhysiologic pulsePhysiologicalPilot ProjectsPlasmidsPolymersPre-Clinical ModelPricePropertyProtocols documentationRegimenReportingResistanceRodentRodent ModelSafetySerumSystemTechnologyTestingTherapeuticTransfectionTranslatingTreatment EfficacyUnited Statesbaseblood-brain barrier disruptionblood-brain barrier penetrationbrain cellbrain parenchymabrain tissueclinical investigationclinical translationclinically relevantdesigndisease phenotypeeffectiveness testinggene therapyglial cell-line derived neurotrophic factorimage guidedimprovedin vivoinnovationmultidisciplinarynanonanoparticlenervous system disorderneurotrophic factornovelpalliativepre-clinicalpreclinical studypreconditioningsealsuccesstherapeutic genetherapeutic nanoparticlestherapeutic proteintherapeutic transgenetherapeutically effectivetransgene expressionvector control
项目摘要
PROJECT SUMMARY
Parkinson's disease (PD) is an increasingly prevalent neurological disorder that currently affects about one
million people in the United States and 10 million worldwide. Despite recent innovations, most advanced
pharmacological and surgical therapeutic regimens remain moderately palliative and symptomatic at best.
Gene therapy has emerged as an alternative promising means to halt the disease progression or potentially
cure the disease. However, clinical trials of PD gene therapy up to this moment have failed to establish a
meaningful therapeutic benefit due to an inability to achieve widespread and efficient gene transfer to the
disease areas within the brain. The significance of this problem is highlighted by an ongoing human trial,
wherein improving the penetration and efficiency of transfection is a primary goal. Further, lacking a reliable
method to deploy gene therapy from the bloodstream to the brain tissue, all clinical studies to date have
employed highly invasive administration modalities involving direct injection of the therapy into the brain. This
reality has precluded the inclusion in clinical trials of early stage PD patients who are more likely to respond to
the therapy. Thus, new methods to overcome long-standing barriers to systemic gene delivery throughout the
PD-associated brain regions, including the tightly sealed blood-brain barrier (BBB) and the dense network of
brain extracellular matrix (ECM), are sorely needed. To this end, we propose innovative delivery approaches
exploiting: (i) clinically operable MR image-guided focused ultrasound (FUS) to transiently open the BBB for
the penetration of gene therapy into the brain tissues and cells in a targeted manner, (ii) DNA-loaded
nanoparticles possessing a unique capability to efficiently spread through the brain ECM to reach and transfect
cells in the disease areas within the brain (i.e. DNA-loaded brain-penetrating nanoparticle or DNA-BPN), and
(iii) FUS-mediated pre-conditioning that further enhances the dispersion of DNA-BPN within the brain by
temporarily reducing ECM resistance. We recently showed in our pilot study that FUS-mediated, targeted BBB
penetration of, and subsequent widespread gene transfer by, our first-generation DNA-BPN resulted in
therapeutically relevant gene therapy of a conventional neurotoxin-based preclinical model of PD. As a next
step towards clinical translation, we here propose to further refine and evaluate our combined delivery strategy
in highly sophisticated and clinically-relevant preclinical models of familial and sporadic PD that closely mimic
pathophysiological features and disease phenotypes observed in human PD. If successful, the proposed
approach could be rapidly translated to the clinic using a gene-encoding a neurotrophic factor (that is currently
under clinical investigation and will be studied here) while additional preclinical studies could be followed to test
the effectiveness of novel genetic targets in these advanced PD models. In addition, the approach could also
be applied to other neurological disorders characterized by highly disseminated disease areas within the brain.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
$ 50.3万 - 项目类别:
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:
10554403 - 财政年份:2021
- 资助金额:
$ 50.3万 - 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:
$ 50.3万 - 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:
$ 50.3万 - 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:
$ 50.3万 - 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:
$ 50.3万 - 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
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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:
$ 50.3万 - 项目类别:
Application of Laser Speckle Flowmetry to Vascular Remodeling
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- 批准号:
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$ 50.3万 - 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:
$ 50.3万 - 项目类别:
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