Biodegradable Mucus Penetrating DNA Nanoparticle for Gene Therapy of CF
用于 CF 基因治疗的可生物降解粘液穿透 DNA 纳米颗粒
基本信息
- 批准号:9229059
- 负责人:
- 金额:$ 39.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2019-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdhesionsAdhesivesAirApicalBiologicalBreathingCellsChronicClinicalClinical ResearchClinical TrialsCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDNADNA deliveryDataDependovirusDiffusionDiseaseDoseEffectivenessEndocytosisEpithelialEpithelial CellsEpitheliumEstersFormulationFutureGastrointestinal tract structureGelGene DeliveryGene ExpressionGene MutationGene TransferGene therapy trialGenesGlandGoldHumanHydration statusIn VitroKineticsLeadLiquid substanceLuciferasesLungLung diseasesMacacaMediatingMembraneModelingMorbidity - disease rateMucous body substanceMusNon-Viral VectorOsmosisOutcomePenetrationPolymersProductionPropertyProteinsReporterSafetySalineSideSourceSputumStructure of parenchyma of lungSurfaceSynthetic GenesSystemTestingToxic effectTransfectionTransgenic OrganismsViralVirusabsorptionacute toxicityadeno-associated viral vectorairway epitheliumaqueousbasecervicovaginalcomparative efficacycystic fibrosis airwaycystic fibrosis patientsepithelial Na+ channelgene delivery systemgene therapygene therapy clinical trialimprovedin vivomortalitymouse modelnanoparticlenoveloverexpressionparticlepre-clinicalpreventpublic health relevancetherapeutic genetransgene expressionuptakevector
项目摘要
DESCRIPTION: Cystic fibrosis (CF) gene therapy can potentially benefit all CF patients, regardless of the specific gene mutation leading to the disease state. However, gene therapy trials, using viral and non-viral vectors, have had disappointing outcomes to date due to inability
to overcome biological barriers, including the purulent sputum gel layer, periciliary layer and epithelial surface. In particular, we previously found that several clinically and preclinically teted viral and non-viral gene vectors are trapped in human CF sputum, which prevents them from reaching and delivering their therapeutic gene cargo to the underlying airway epithelium. We recently developed two delivery strategies: (i) ultra-small DNA-loaded nanoparticles, called mucus-penetrating DNA nanoparticles (DNA-MPP) that efficiently penetrate human CF sputum and (ii) mildly hypotonic aqueous vehicles, which further improves DNA-MPP penetration through the sputum gel layer and periciliary layer via osmosis-driven fluid absorption, and enhances DNA-MPP uptake by the airway epithelium via the regulatory volume decrease mechanism. We found that the combination of these two approaches led to efficient gene transfer to the airway epithelium of normal mice in vivo and primary human airway cells in vitro. Here we propose to further develop and validate our combined approach in relevant in vitro and in vivo settings. To this end, we will evaluate CFTR gene transfer to CF human primary airway epithelium grown at air-liquid interface and in the lung airways of CF mouse model thoroughly characterized for its CF-like lung diseases. We will also determine whether our delivery strategies allow persistent transgene expression upon a single and repeated dosing without eliciting acute and chronic toxicity. If we are successful, we will test our strategies in macaques
and potentially clinical studies in the future.
产品说明:囊性纤维化(CF)基因治疗可能使所有CF患者受益,无论导致疾病状态的特定基因突变如何。然而,使用病毒和非病毒载体的基因治疗试验迄今为止由于无法实现基因治疗,结果令人失望。
克服生物屏障,包括脓痰凝胶层、纤毛周层和上皮表面。特别是,我们以前发现,几个临床和临床前测试的病毒和非病毒基因载体被困在人CF痰液中,这阻止了它们到达并将其治疗基因货物递送到下面的气道上皮。我们最近制定了两项交付战略:(i)负载DNA的超小纳米颗粒,称为粘液穿透DNA纳米颗粒(DNA-MPP),其有效地穿透人CF痰液,和(ii)轻度低渗水性载体,其通过痰液驱动的流体吸收进一步改善DNA-MPP穿透痰液凝胶层和纤毛周层,并通过调节性容积减少机制增强气道上皮细胞对DNA-MPP的摄取。我们发现,这两种方法的组合导致有效的基因转移到正常小鼠的气道上皮细胞在体内和原代人气道细胞在体外。在这里,我们建议进一步开发和验证我们的组合方法在相关的体外和体内环境。为此,我们将评估CFTR基因转移到在气液界面生长的CF人原代气道上皮细胞和CF小鼠模型的肺气道中,其特征在于其CF样肺病。我们还将确定我们的递送策略是否允许在单次和重复给药后持续的转基因表达而不引起急性和慢性毒性。如果我们成功了,我们将在猕猴身上测试我们的策略
以及将来可能的临床研究。
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 }}
Justin S. Hanes其他文献
Justin S. Hanes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('Justin S. Hanes', 18)}}的其他基金
Focused ultrasound pre-conditioning for augmented nanoparticle penetration in infiltrative gliomas
聚焦超声预处理增强纳米颗粒在浸润性神经胶质瘤中的渗透
- 批准号:
10375573 - 财政年份:2021
- 资助金额:
$ 39.64万 - 项目类别:
Focused ultrasound pre-conditioning for augmented nanoparticle penetration in infiltrative gliomas
聚焦超声预处理增强纳米颗粒在浸润性神经胶质瘤中的渗透
- 批准号:
10210648 - 财政年份:2021
- 资助金额:
$ 39.64万 - 项目类别:
Focused ultrasound pre-conditioning for augmented nanoparticle penetration in infiltrative gliomas
聚焦超声预处理增强纳米颗粒在浸润性神经胶质瘤中的渗透
- 批准号:
10541232 - 财政年份:2021
- 资助金额:
$ 39.64万 - 项目类别:
Targeted Delivery of Brain Penetrating DNA Nanoparticles to Brain Tumors
脑部穿透性 DNA 纳米颗粒靶向递送至脑肿瘤
- 批准号:
9083426 - 财政年份:2016
- 资助金额:
$ 39.64万 - 项目类别:
Targeted Delivery of Brain Penetrating DNA Nanoparticles to Brain Tumors
脑部穿透性 DNA 纳米颗粒靶向递送至脑肿瘤
- 批准号:
9260870 - 财政年份:2016
- 资助金额:
$ 39.64万 - 项目类别:
Targeted Delivery of Brain Penetrating DNA Nanoparticles to Brain Tumors
脑部穿透性 DNA 纳米颗粒靶向递送至脑肿瘤
- 批准号:
9891031 - 财政年份:2016
- 资助金额:
$ 39.64万 - 项目类别:
Biodegradable Mucus Penetrating DNA Nanoparticle for Gene Therapy of CF
用于 CF 基因治疗的可生物降解粘液穿透 DNA 纳米颗粒
- 批准号:
8863900 - 财政年份:2015
- 资助金额:
$ 39.64万 - 项目类别:
Mucus Microstructure and Osmotic Pressure: Biomarkers for CB in COPD
粘液微观结构和渗透压:COPD 中 CB 的生物标志物
- 批准号:
8852864 - 财政年份:2015
- 资助金额:
$ 39.64万 - 项目类别:
Glutaminase Inhibitor Drug Discovery and Nanoparticle-Based Delivery for Pancreatic Cancer Therapy
谷氨酰胺酶抑制剂药物的发现和基于纳米颗粒的胰腺癌治疗递送
- 批准号:
9188044 - 财政年份:2015
- 资助金额:
$ 39.64万 - 项目类别:
Glutaminase Inhibitor Drug Discovery and Nanoparticle-Based Delivery for Pancreatic Cancer Therapy
谷氨酰胺酶抑制剂药物的发现和基于纳米颗粒的胰腺癌治疗递送
- 批准号:
9028315 - 财政年份:2015
- 资助金额:
$ 39.64万 - 项目类别:
相似海外基金
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y004841/1 - 财政年份:2024
- 资助金额:
$ 39.64万 - 项目类别:
Research Grant
Defining a role for non-canonical mTORC1 activity at focal adhesions
定义非典型 mTORC1 活性在粘着斑中的作用
- 批准号:
BB/Y001427/1 - 财政年份:2024
- 资助金额:
$ 39.64万 - 项目类别:
Research Grant
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y005414/1 - 财政年份:2024
- 资助金额:
$ 39.64万 - 项目类别:
Research Grant
Development of a single-use, ready-to-use, sterile, dual chamber, dual syringe sprayable hydrogel to prevent postsurgical cardiac adhesions.
开发一次性、即用型、无菌、双室、双注射器可喷雾水凝胶,以防止术后心脏粘连。
- 批准号:
10669829 - 财政年份:2023
- 资助金额:
$ 39.64万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10587090 - 财政年份:2023
- 资助金额:
$ 39.64万 - 项目类别:
Improving Maternal Outcomes of Cesarean Delivery with the Prevention of Postoperative Adhesions
通过预防术后粘连改善剖宫产的产妇结局
- 批准号:
10821599 - 财政年份:2023
- 资助金额:
$ 39.64万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10841832 - 财政年份:2023
- 资助金额:
$ 39.64万 - 项目类别:
Prevention of Intraabdominal Adhesions via Release of Novel Anti-Inflammatory from Surface Eroding Polymer Solid Barrier
通过从表面侵蚀聚合物固体屏障中释放新型抗炎剂来预防腹内粘连
- 批准号:
10532480 - 财政年份:2022
- 资助金额:
$ 39.64万 - 项目类别:
I-Corps: A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions
I-Corps:一种可喷雾的组织结合水凝胶,可防止术后心脏粘连
- 批准号:
10741261 - 财政年份:2022
- 资助金额:
$ 39.64万 - 项目类别:
Sprayable Polymer Blends for Prevention of Site Specific Surgical Adhesions
用于预防特定部位手术粘连的可喷涂聚合物共混物
- 批准号:
10674894 - 财政年份:2022
- 资助金额:
$ 39.64万 - 项目类别: