A Nanocarrier Platform for Targeting Schlemm's Canal Cells
用于靶向施累姆氏管细胞的纳米载体平台
基本信息
- 批准号:10705690
- 负责人:
- 金额:$ 54.37万
- 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 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:ActinsAddressAdverse effectsAffectAnimal ModelAnimalsAntihypertensive AgentsAqueous HumorAttentionBlood VesselsBolus InfusionCellsClinicalClinical TrialsCorneaCorneal EndotheliumCytoskeletonDiagnosticDrug CarriersDrug Delivery SystemsDrug vehicleEndothelial CellsEngineeringEvaluationExhibitsEyeFormulationFrequenciesFutureGene DeliveryGlaucomaHistologyHourHumanHydrogelsHyperemiaIn VitroInjectableInjectionsMeasuresMechanicsMicellesMicroscopyModelingMonkeysMusOcular HypotensionOptical Coherence TomographyPathway interactionsPatientsPerfusionPharmaceutical PreparationsPhenotypePhysiologic Intraocular PressurePlasmidsPopulationPrimary Open Angle GlaucomaReducing AgentsReporterResistanceRetinaRho-associated kinaseSpecificityStructure of sinus venosus of scleraSystemTherapeuticTherapeutic AgentsTherapeutic EffectTissuesTopical applicationToxic effectTransfectionVascular Endothelial CellVisible RadiationWorkanterior chambercellular targetingcorneal epitheliumdosageefficacy evaluationeye chambergene delivery systemgene therapyin vivokinase inhibitorlatrunculin Amouse modelnanocarriernanoscalenon-viral gene deliverynonhuman primatenovelocular hypotensivepressurerhoA GTP-Binding Proteinside effectsuperresolution microscopytargeted deliverytargeted treatmenttherapeutic targettonometryultrasounduptake
项目摘要
PROJECT SUMMARY
Nanoscale drug carriers (i.e. nanocarriers) have attracted much attention for their ability to transport diverse
therapeutic and diagnostic agents and to selectively target specific cells and tissues. This increased specificity
can have significant clinical implications, including decreased side effects and lower dosages with higher
potency. Schlemm's canal (SC) endothelial cells hold promise as a cellular target for glaucoma therapy, as their
mechanical stiffness is associated with modulation of intraocular pressure (IOP). Rho kinase inhibitors and actin-
depolymerizing agents reduce endothelial cell stiffness and significantly lower IOP in animals and humans with
several now approved for clinical use. However, these agents are associated with significant side effects,
including conjunctival hyperemia and corneal verticillata. Studies show that >50% of patients treated with these
therapeutics exhibit adverse side effects. Targeted nanocarrier delivery systems may address these issues but
are not currently capable of passing through the corneal epithelium and must therefore be administered via
intraocular injection. As frequent eye injections would not be well tolerated by patients, sustained intraocular
delivery systems are needed to minimize the frequency of drug administration. Gene therapy targets for
treatment of ocular hypotension have emerged, holding promise for a future glaucoma cure following a single
intraocular injection, but a targeted gene delivery system is needed to enhance selective transfection of SC cells.
A significant need therefore exists for both sustained nanocarrier delivery systems and gene delivery systems
for intraocular strategies targeting the SC. With these needs in mind, the objective of this proposal is to engineer
a scalable, customizable, synthetic nanocarrier platform that can be adapted to transport diverse therapeutic
agents to outflow pathway cells with controllable release rates. Successful completion of this work will result in
the first delivery system for sustained intraocular release of nanocarriers, a novel nonviral gene delivery platform
for selective transfection of SC cells, and completion of nonhuman primate studies to justify clinical trials of these
delivery systems in humans.
The following Specific Aims will be completed:
Aim 1: Optimize the duration of therapeutic effect for nanocarriers targeting Schlemm’s canal cells while avoiding
side effects and toxicity within the cornea and vascular tissues in mouse eyes.
Aim 2: Demonstrate nonviral transfection of Schlemm's canal cells in vivo using targeted nanocarriers without
affecting nearby ocular tissues in mice
Aim 3: Demonstrate that targeted nanocarriers containing latrunculin-A significantly increase conventional
outflow facility and lower IOP in nonhuman primates without adverse effects.
项目总结
纳米级药物载体(即纳米载体)因其能够输送不同种类的药物而备受关注
治疗和诊断药物,并选择性地靶向特定的细胞和组织。这增加了专一性
可以有显著的临床意义,包括减少副作用和较低的剂量与较高的
威力。Schlemm管(SC)内皮细胞有望成为青光眼治疗的细胞靶点,因为它们
机械僵硬与眼压的调节有关。Rho激酶抑制剂和肌动蛋白-
解聚剂降低内皮细胞硬度并显著降低动物和人类的眼压
其中几种现已获准临床使用。然而,这些药物与显著的副作用有关,
包括结膜充血和角膜轮状疱疹。研究表明,使用这些药物治疗的患者中有50%
治疗药物表现出不良副作用。靶向纳米载体递送系统可能会解决这些问题,但
目前不能通过角膜上皮,因此必须通过
眼内注射。由于频繁的眼部注射不会被患者很好地耐受,所以持续的眼内注射
需要有给药系统,以最大限度地减少给药的频率。基因治疗的靶点
眼压过低的治疗方法已经出现,有望在单次治疗后治愈青光眼。
眼内注射,但需要一个靶向的基因输送系统来加强对SC细胞的选择性转染。
因此,对持续纳米载体递送系统和基因递送系统都存在重大需求
以SC为目标的眼内策略。考虑到这些需求,本提案的目标是设计
可扩展、可定制的合成纳米载体平台,可用于运输不同的治疗药物
药物以可控的释放速率流出途径细胞。这项工作的成功完成将导致
新型非病毒基因递送平台--纳米载体眼内缓释系统的研制
用于选择性地转导SC细胞,以及完成非人类灵长类研究以证明这些临床试验的合理性
人体内的递送系统。
将完成以下具体目标:
目的1:优化靶向Schlemm管细胞的纳米载体的治疗持续时间,同时避免
小鼠眼部角膜和血管组织的副作用和毒性。
目的2:利用靶向纳米载体在体内验证非病毒转染性Schlemm管细胞
对小鼠邻近眼组织的影响
目的3:证明含有LATRUNC-A的靶向纳米载体显著增加了传统的
非人类灵长类动物的流出便利和较低的眼压,没有不良影响。
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 }}
MARK JOHNSON其他文献
MARK JOHNSON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('MARK JOHNSON', 18)}}的其他基金
A Nanocarrier Platform for Targeting Schlemm's Canal Cells
用于靶向施累姆氏管细胞的纳米载体平台
- 批准号:
10539739 - 财政年份:2022
- 资助金额:
$ 54.37万 - 项目类别:
The Mechanical Basis of Primary Open Angle Glaucoma
原发性开角型青光眼的力学基础
- 批准号:
7941709 - 财政年份:2009
- 资助金额:
$ 54.37万 - 项目类别:
The Mechanical Basis of Primary Open Angle Glaucoma
原发性开角型青光眼的力学基础
- 批准号:
7698588 - 财政年份:2009
- 资助金额:
$ 54.37万 - 项目类别:
The Mechanical Basis of Primary Open Angle Glaucoma
原发性开角型青光眼的力学基础
- 批准号:
8136021 - 财政年份:2009
- 资助金额:
$ 54.37万 - 项目类别:
The Mechanical Basis of Primary Open Angle Glaucoma
原发性开角型青光眼的力学基础
- 批准号:
8542851 - 财政年份:2009
- 资助金额:
$ 54.37万 - 项目类别:
The Mechanical Basis of Primary Open Angle Glaucoma
原发性开角型青光眼的力学基础
- 批准号:
8009012 - 财政年份:2009
- 资助金额:
$ 54.37万 - 项目类别:
The Mechanical Basis of Primary Open Angle Glaucoma
原发性开角型青光眼的力学基础
- 批准号:
8323411 - 财政年份:2009
- 资助金额:
$ 54.37万 - 项目类别:
SBIR TOPIC 257, INSTRUMENTS AND DEVICES THAT PRESERVE MOLECULAR PROFILES IN TUMO
SBIR 主题 257,保留 TUMO 中分子特征的仪器和设备
- 批准号:
7962681 - 财政年份:2009
- 资助金额:
$ 54.37万 - 项目类别:
Bioengineering of Transport Across Bruch's Membrance
跨布鲁赫膜运输的生物工程
- 批准号:
6891272 - 财政年份:2003
- 资助金额:
$ 54.37万 - 项目类别:
Bioengineering of Transport Across Bruch's Membrance
跨布鲁赫膜运输的生物工程
- 批准号:
6602199 - 财政年份:2003
- 资助金额:
$ 54.37万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 54.37万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 54.37万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 54.37万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 54.37万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 54.37万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 54.37万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 54.37万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 54.37万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 54.37万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 54.37万 - 项目类别:
Research Grant