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.
项目摘要
帕金森病(PD)是一种日益普遍的神经系统疾病,目前约有1
美国有1000万人,全世界有1000万人。尽管最近的创新,大多数先进的
药理学和手术治疗方案最多保持适度的姑息和对症治疗。
基因治疗已经成为一种替代的有希望的手段,以阻止疾病的进展或潜在的
治愈疾病然而,到目前为止,PD基因治疗的临床试验未能建立一个有效的治疗方法。
由于不能实现广泛和有效的基因转移到
大脑中的疾病区域。正在进行的人体试验突出了这个问题的重要性,
其中提高转染的穿透性和效率是主要目标。此外,缺乏可靠的
方法部署基因治疗从血液到脑组织,所有的临床研究,到目前为止,
采用高度侵入性的给药方式,包括将治疗直接注射到脑中。这
事实上,临床试验中排除了早期PD患者,这些患者更有可能对
治疗因此,克服整个过程中系统性基因递送的长期障碍的新方法
PD相关的脑区,包括紧密封闭的血脑屏障(BBB)和密集的神经网络。
脑细胞外基质(ECM)是非常需要的。为此,我们提出了创新的交付方法,
利用:(i)临床上可操作的MR图像引导聚焦超声(FUS)瞬时打开BBB,
基因治疗以靶向方式渗透到脑组织和细胞中,(ii)DNA负载的
纳米颗粒具有独特的能力,可以有效地通过大脑ECM扩散,
- 脑内疾病区域中的细胞(即DNA-负载的脑穿透纳米颗粒或DNA-BPN),和
(iii)FUS介导的预处理通过以下方式进一步增强DNA-BPN在脑内的分散:
暂时降低ECM电阻。我们最近在我们的初步研究中表明,FUS介导的靶向BBB
我们的第一代DNA-BPN的渗透和随后的广泛基因转移导致了
常规的基于神经毒素的PD临床前模型的治疗相关基因疗法。作为下一个
迈向临床转化,我们在此建议进一步完善和评估我们的联合交付策略
在家族性和散发性PD的高度复杂和临床相关的临床前模型中,
在人类PD中观察到的病理生理学特征和疾病表型。如果成功,建议
这种方法可以迅速转化为临床使用的基因编码的神经营养因子(即目前
正在进行临床研究,并将在此进行研究),同时可以进行其他临床前研究,
新型遗传靶点在这些高级PD模型中的有效性。此外,该方法还可以
可应用于以脑内高度扩散的疾病区域为特征的其他神经障碍。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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
- 资助金额:
$ 50.3万 - 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:
$ 50.3万 - 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:
$ 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:
相似海外基金
I-Corps: Translation Potential of Peptidic Ensembles as Novel Bio-adhesives
I-Corps:肽整体作为新型生物粘合剂的转化潜力
- 批准号:
2409620 - 财政年份:2024
- 资助金额:
$ 50.3万 - 项目类别:
Standard Grant
Architectural design of active adhesives
活性粘合剂的结构设计
- 批准号:
2403716 - 财政年份:2024
- 资助金额:
$ 50.3万 - 项目类别:
Standard Grant
Design of non-swellable adhesives for brain surgery using cyclodextrin inclusion polymer
使用环糊精包合物聚合物脑外科不可溶胀粘合剂的设计
- 批准号:
23H01718 - 财政年份:2023
- 资助金额:
$ 50.3万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Meta-material adhesives for improved performance and functionalisation of bondlines
超材料粘合剂可提高粘合层的性能和功能化
- 批准号:
EP/W019450/1 - 财政年份:2023
- 资助金额:
$ 50.3万 - 项目类别:
Fellowship
Light-propelled dental adhesives with enhanced bonding capability
具有增强粘合能力的光驱动牙科粘合剂
- 批准号:
10741660 - 财政年份:2023
- 资助金额:
$ 50.3万 - 项目类别:
DMREF: Accelerating the Design of Adhesives with Nanoscale Control of Thermomechanical Properties
DMREF:通过热机械性能的纳米级控制加速粘合剂的设计
- 批准号:
2323317 - 财政年份:2023
- 资助金额:
$ 50.3万 - 项目类别:
Continuing Grant
Mag-Cure: A novel method for magnetically induced bonding and de-bonding of thermoset adhesives in the Automotive Industry
Mag-Cure:汽车行业中热固性粘合剂磁感应粘合和脱粘的新方法
- 批准号:
10062336 - 财政年份:2023
- 资助金额:
$ 50.3万 - 项目类别:
Collaborative R&D
Biodegradable, Biocompatible Pressure Sensitive Adhesives
可生物降解、生物相容性压敏粘合剂
- 批准号:
10677869 - 财政年份:2022
- 资助金额:
$ 50.3万 - 项目类别:
Poly(glycerol carbonate) pressure sensitive adhesives for the in vivo closure of alveolar pleural fistulae
用于体内闭合肺泡胸膜瘘的聚(甘油碳酸酯)压敏粘合剂
- 批准号:
10746743 - 财政年份:2022
- 资助金额:
$ 50.3万 - 项目类别:
Enhanced bio-production of difficult to make peptide ingredients for specialty adhesives and personal care
增强用于特种粘合剂和个人护理品的难以制造的肽成分的生物生产
- 批准号:
10021363 - 财政年份:2022
- 资助金额:
$ 50.3万 - 项目类别:
Investment Accelerator