Acoustically targeted, high-resolution, site-specific, transretinal delivery of macromolecules
声学靶向、高分辨率、位点特异性、经视网膜输送大分子
基本信息
- 批准号:10706971
- 负责人:
- 金额:$ 19.05万
- 依托单位:
- 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:2022-09-30 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcousticsAcuteAffectAgeAnimal ExperimentationAnimalsBlindnessBlood - brain barrier anatomyBlood CirculationBlood capillariesBlood-Retinal BarrierBrainCellsClinicClinicalClinical TrialsContractsContrast MediaDefinityDiameterDiseaseDrug Delivery SystemsDyesEvans blue stainEyeEye diseasesFDA approvedFocused UltrasoundFrequenciesGene DeliveryGene ExpressionGene Transduction AgentGenesGenetic MaterialsHemorrhageHistologyHourHumanInflammationInheritedInjectionsIntravenousLong-Term EffectsMethodologyMethodsMicrobubblesMuller&aposs cellMusOperative Surgical ProceduresOphthalmologic Surgical ProceduresOutcomePatientsPeripheralPersonsPetechiaePrevalenceProceduresProcessProteinsProtocols documentationRPE65 proteinReactionRegional DiseaseReporter GenesResolutionRetinaRetinal DetachmentRetinal DiseasesRetinal Ganglion CellsRisk ReductionRodentSafetySiteSpecialistSpecificitySurgeonSystemTechniquesTestingThickTight JunctionsTissuesTropismVeinsViralViral VectorVirusWorkadeno-associated viral vectorbonecell typecellular transductiondelivery vehicledetectorexperiencegene replacement therapygene therapyimprovedinnovationintravenous injectionmacromoleculenanometerpressurepromoterprototypereal time monitoringretinal damagesight restorationskillssmall moleculestemsubretinal injectionsuccesstherapeutic genetransduction efficiencyultrasound
项目摘要
Project summary
We propose to develop a method of non-surgical, spatially precise, ultrasound-enhanced delivery of
macromolecules to the retina. The need for such delivery methods stems from the prevalence of recent success
in the treatment of retinal disorders by gene therapy. Inherited retinal diseases affect several million people
worldwide and often result in vision loss and blindness. Most retinal disorders are incurable, but recent advances
in gene therapy have restored vision and hope to many. In animal research, gene delivery to the eye has also
helped uncover mechanisms of retinal disease. However, in both the clinic and animal research, delivery of
genes to the eye is challenging. Currently, the delivery of genetic material requires surgery performed by a
vitreo-retinal surgeon to access the subretinal space for the injection of genetic material. This process is
technically difficult and can result in serious complications. Here, we will develop a new method of
macromolecule and gene delivery to the retina that does not require eye surgery or intraocular injection of genetic
material. In this method called, Enhanced Transretinal Ultrasound Delivery (ETUDE), we combine our
experience in focused-ultrasound gene delivery and retinal disorders. In ETUDE, focused ultrasound (FUS) is
targeted with high precision to a small region of retina. Then, a clinically-approved microbubble contrast agent
is injected through a peripheral vein. In the brain, such a contrast agent responds to ultrasound and exerts mild
pressure on interior lumen of capillaries. This pressure then opens the tight junctions in blood-brain barrier (BBB)
and allows for free passage of molecules up to ~20 nanometers in diameter. This BBB opening lasts for several
hours and has was previously used for delivery of small molecules, proteins, and viral vectors. The retina
contains a similar vasculature referred to as a blood-retinal barrier (BRB). We hypothesize that BRB and BBB
react similarly to the FUS in presence of an ultrasound contrast agent and will similarly enable site-specific
delivery of molecules to the eye. To enable high-precision, high-safety gene delivery to the eye we propose to
use an innovative method of spatial targeting of ultrasound. We will use high-frequency ultrasound and record
the ultrasound echo of the microbubble contrast agent in the retina. We expect to target retinal ~300-micron
sized regions spanning the retinal thickness in mice. Throughout this project, we will develop safe protocols for
ETUDE, and quantitatively characterize its efficiency, spatial precision, and any potential tissue damage in gene
delivery of intravenously applied viral vectors, and enable cell-type specific gene delivery to retinal ganglion cells
(RGC). If successful, we will have enabled a safe, non-surgical, site-specific, gene and macromolecule delivery
to specific retinal cell-types.
项目概要
我们建议开发一种非手术、空间精确、超声增强的方法
大分子到达视网膜。对此类递送方法的需求源于最近成功的普遍现象
通过基因疗法治疗视网膜疾病。遗传性视网膜疾病影响数百万人
在世界范围内,经常导致视力丧失和失明。大多数视网膜疾病无法治愈,但最新进展
基因治疗使许多人恢复了视力和希望。在动物研究中,基因传递到眼睛也已
帮助揭示视网膜疾病的机制。然而,在临床和动物研究中,
基因对眼睛来说是具有挑战性的。目前,遗传物质的传递需要由手术人员进行
玻璃体视网膜外科医生进入视网膜下腔注射遗传物质。这个过程是
技术上很困难,并且可能导致严重的并发症。在这里,我们将开发一种新方法
将大分子和基因传递到视网膜,不需要眼科手术或眼内注射基因
材料。在这种称为增强型经视网膜超声传输 (ETUDE) 的方法中,我们结合了我们的
在聚焦超声基因传递和视网膜疾病方面拥有丰富的经验。在 ETUDE 中,聚焦超声 (FUS) 是
高精度地瞄准视网膜的一小块区域。然后,临床批准的微泡造影剂
通过外周静脉注射。在大脑中,这种造影剂会对超声波做出反应并发挥温和的作用
毛细血管内腔的压力。然后,该压力打开血脑屏障 (BBB) 中的紧密连接
并允许直径达~20纳米的分子自由通过。这个 BBB 开口持续数个
小时和曾用于递送小分子、蛋白质和病毒载体。视网膜
包含类似的脉管系统,称为血视网膜屏障(BRB)。我们假设 BRB 和 BBB
在存在超声造影剂的情况下,其反应与 FUS 类似,并且同样能够实现位点特异性
将分子输送到眼睛。为了实现高精度、高安全性的基因递送至眼睛,我们建议:
使用超声空间定位的创新方法。我们将使用高频超声波并记录
微泡造影剂在视网膜中的超声回声。我们期望以约 300 微米的视网膜为目标
跨越小鼠视网膜厚度的大小区域。在整个项目中,我们将开发安全协议
ETUDE,并定量表征其效率、空间精度以及基因中任何潜在的组织损伤
静脉注射病毒载体的递送,并使细胞类型特异性基因递送至视网膜神经节细胞
(研究资助局)。如果成功,我们将实现安全、非手术、特定位点的基因和大分子递送
特定的视网膜细胞类型。
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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Benjamin J Frankfort其他文献
Benjamin J Frankfort的其他文献
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{{ truncateString('Benjamin J Frankfort', 18)}}的其他基金
An in vitro/in vivo system for targeted retinal ganglion cell subtype manipulation
用于靶向视网膜神经节细胞亚型操作的体外/体内系统
- 批准号:
10354977 - 财政年份:2022
- 资助金额:
$ 19.05万 - 项目类别:
An in vitro/in vivo system for targeted retinal ganglion cell subtype manipulation
用于靶向视网膜神经节细胞亚型操作的体外/体内系统
- 批准号:
10546443 - 财政年份:2022
- 资助金额:
$ 19.05万 - 项目类别:
Acoustically targeted, high-resolution, site-specific, transretinal delivery of macromolecules
声学靶向、高分辨率、位点特异性、经视网膜输送大分子
- 批准号:
10373250 - 财政年份:2022
- 资助金额:
$ 19.05万 - 项目类别:
Brain and eye pressure-induced optic nerve and retinal degeneration
脑和眼压引起的视神经和视网膜变性
- 批准号:
10665661 - 财政年份:2015
- 资助金额:
$ 19.05万 - 项目类别:
Brain and eye pressure-induced optic nerve and retinal degeneration
脑和眼压引起的视神经和视网膜变性
- 批准号:
10224691 - 财政年份:2015
- 资助金额:
$ 19.05万 - 项目类别:
Brain and eye pressure-induced optic nerve and retinal degeneration
脑和眼压引起的视神经和视网膜变性
- 批准号:
10475612 - 财政年份:2015
- 资助金额:
$ 19.05万 - 项目类别:
RETINAL GANGLION CELL AND AMACRINE CELL FUNCTION IN MOUSE MODELS OF ELEVATED INTR
INTR升高小鼠模型中视网膜神经节细胞和无精细胞的功能
- 批准号:
8703704 - 财政年份:2011
- 资助金额:
$ 19.05万 - 项目类别:
RETINAL GANGLION CELL AND AMACRINE CELL FUNCTION IN MOUSE MODELS OF ELEVATED INTR
INTR升高小鼠模型中视网膜神经节细胞和无精细胞的功能
- 批准号:
8885832 - 财政年份:2011
- 资助金额:
$ 19.05万 - 项目类别:
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