Development of AAV-AXN-007 gene therapy to treat glaucoma.
开发 AAV-AXN-007 基因疗法来治疗青光眼。
基本信息
- 批准号:10547231
- 负责人:
- 金额:$ 29.88万
- 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:2022-09-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:Academic Medical CentersAction PotentialsAddressAdultAgeAgreementAnimal ModelAttenuatedAutopsyAxonBlindnessBostonBrainCRISPR screenCRISPR/Cas technologyCell DeathCell LineCellsChronicClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsComplexConserved SequenceContralateralCrush InjuryDevelopmentDiseaseDown-RegulationDrug KineticsEyeFamilyFoundationsGene DeletionGenesGenetic ScreeningGlaucomaGoalsHumanIn VitroInjectionsLeadLegal patentMAPK8 geneMeasurementMeasuresMediatingMedicalMedical Care CostsMicrospheresMitogen-Activated Protein Kinase KinasesModelingMusN-terminalNerveNerve CrushNeurodegenerative DisordersNeuronsOperative Surgical ProceduresOphthalmologyOptic NerveOpticsPathologicPathologyPathway interactionsPatientsPediatric HospitalsPersonsPharmacologyPhasePhosphotransferasesPhysiologic Intraocular PressurePlasmidsPopulationPrevalenceProteinsPublishingRattusReflex actionReportingRetinaRetinal DiseasesRetinal Ganglion CellsRisk FactorsRodentSaimiriSalineScaffolding ProteinSecureSignal TransductionSmall Business Innovation Research GrantStressTechniquesTestingTherapeuticTimeTissuesTranslationsVirusVisionage related neurodegenerationagedanterograde transportaxon injurybasecell typedrug metabolismeffectiveness evaluationefficacy testinggene therapygenetic testingimprovedin vivoin vivo evaluationinternal controlintravitreal injectionknock-downlead candidatemedical schoolsmodifiable risknerve damageneuroblastoma cellneuroprotectionnew therapeutic targetnonhuman primatenoveloptic nerve disorderpharmacodynamic biomarkerpreservationpreventprofessorprototyperetinal ganglion cell degenerationsmall hairpin RNAsocioeconomicsstandard of carestress kinasesuccesstherapeutic genevectorvector control
项目摘要
Development of AAV-AXN-007 gene therapy to treat Glaucoma
Abstract:
Glaucoma represents the world’s leading cause of irreversible blindness, with its prevalence increasing as the
population ages. Vision loss in glaucoma is caused by a progressive degeneration of retinal ganglion cells
(RGCs), yet there are no approved therapies that can directly prevent RGC loss. Because elevated intraocular
pressure (IOP) is only known modifiable risk factor, current standard of care involves IOP-lowering treatments
via pharmacological and surgical approaches. This chronic, progressive, age-related neurodegenerative
disorder is an urgent, unmet, global and growing problem, with the number of people worldwide suffering with
glaucoma expected to double to ~120 million by 2040, and the annual medical costs of glaucoma in US
projected treble to >$17 billion by 2050. To address this escalating medical and socioeconomic burden, and to
improve lives of glaucoma patients and their families, novel disease-modifying therapies are needed.
Progressive RGC degeneration in glaucoma is thought to result from an intrinsic sensitivity of RGCs
that over time succumb to the chronic pathological stresses of this complex neurodegenerative disease.
Intervening during this time period in the remaining RGCs of glaucoma patients could prevent their
degeneration. To identify new therapeutic targets, an unbiased in vivo AAV2-CRISPR/Cas9 screen of >2,000
genes (tested one-by-one) for RGC neuroprotection in the mouse optic nerve crush model was conducted.
This forward genetic screen in an animal model of optic neuropathy discovered a neuroprotective hit gene that,
when targeted with AAV2-sgRNA, could prevent RGCs from degeneration following axon damage.
Additionally, this pathway has been reported to be activated in post-mortem retinal tissue from glaucoma
patients and after optic nerve damage. In this SBIR application, our goal is to validate and test a novel
neuroprotective target and AAV2-AXN-007 gene therapeutic approach for its ability to protect RGCs, their
axons and visual function in the widely-used mouse microbead occlusion model of glaucoma.
AAV-AXN-007基因治疗青光眼的研究进展
摘要:
青光眼是世界上导致不可逆性失明的主要原因,随着
人口老龄化。青光眼的视力丧失是由视网膜神经节细胞进行性退化引起的
(RGC),但目前还没有得到批准的治疗方法可以直接防止RGC的损失。因为升高的眼内
眼压(IOP)只是已知的可改变的危险因素,目前的护理标准包括降眼压治疗
通过药理学和外科方法。这种慢性的、进行性的、与年龄相关的神经退行性变
混乱是一个紧急的、未得到满足的、全球性的和日益严重的问题,全世界有许多人患有
到2040年,青光眼预计将翻一番,达到1.2亿美元,美国青光眼的年医疗费用
预计到2050年将翻两番,达到170亿美元。应对这一不断上升的医疗和社会经济负担,并
为了改善青光眼患者及其家人的生活,需要新的疾病修正疗法。
青光眼的进行性RGC变性被认为是由于RGC的内在敏感性所致
随着时间的推移,会屈服于这种复杂的神经退行性疾病的慢性病理压力。
在这段时间内对青光眼患者剩余的视网膜节细胞进行干预可以预防其
退化。为了寻找新的治疗靶点,一个无偏的体内AAV2-CRISPR/Cas9筛选>;2000
在小鼠视神经挤压模型中,对RGC神经保护基因进行了逐一检测。
在视神经病变动物模型中的这一正向遗传筛查发现了一种神经保护性HIT基因,
当以AAV2-sgRNA为靶点时,可以防止视网膜节细胞在轴突损伤后变性。
此外,据报道,这一途径在青光眼死后视网膜组织中被激活。
患者和视神经损伤后。在这个SBIR应用程序中,我们的目标是验证和测试一个新的
神经保护靶点及AAV2-AXN-007基因治疗对视网膜神经节细胞的保护作用
广泛使用的小鼠微珠阻塞青光眼模型中的轴突和视觉功能。
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 }}
Shane Hegarty其他文献
Shane Hegarty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('Shane Hegarty', 18)}}的其他基金
Development of oral KCC2 enhancer drug for treatment of painful diabetic neuropathy
开发用于治疗疼痛性糖尿病神经病变的口服 KCC2 增强剂药物
- 批准号:
10699218 - 财政年份:2023
- 资助金额:
$ 29.88万 - 项目类别:
相似海外基金
Kilohertz volumetric imaging of neuronal action potentials in awake behaving mice
清醒行为小鼠神经元动作电位的千赫兹体积成像
- 批准号:
10515267 - 财政年份:2022
- 资助金额:
$ 29.88万 - 项目类别:
Signal processing in horizontal cells of the mammalian retina – coding of visual information by calcium and sodium action potentials
哺乳动物视网膜水平细胞的信号处理 â 通过钙和钠动作电位编码视觉信息
- 批准号:
422915148 - 财政年份:2019
- 资助金额:
$ 29.88万 - 项目类别:
Research Grants
CAREER: Resolving action potentials and high-density neural signals from the surface of the brain
职业:解析来自大脑表面的动作电位和高密度神经信号
- 批准号:
1752274 - 财政年份:2018
- 资助金额:
$ 29.88万 - 项目类别:
Continuing Grant
Development of Nanosheet-Based Wireless Probes for Multi-Simultaneous Monitoring of Action Potentials and Neurotransmitters
开发基于纳米片的无线探针,用于同时监测动作电位和神经递质
- 批准号:
18H03539 - 财政年份:2018
- 资助金额:
$ 29.88万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Population Imaging of Action Potentials by Novel Two-Photon Microscopes and Genetically Encoded Voltage Indicators
通过新型双光子显微镜和基因编码电压指示器对动作电位进行群体成像
- 批准号:
9588470 - 财政年份:2018
- 资助金额:
$ 29.88万 - 项目类别:
Enhanced quantitative imaging of compound action potentials in multi-fascicular peripheral nerve with fast neural Electrical Impedance Tomography enabled by 3D multi-plane softening bioelectronics
通过 3D 多平面软化生物电子学实现快速神经电阻抗断层扫描,增强多束周围神经复合动作电位的定量成像
- 批准号:
10009724 - 财政年份:2018
- 资助金额:
$ 29.88万 - 项目类别:
Enhanced quantitative imaging of compound action potentials in multi-fascicular peripheral nerve with fast neural Electrical Impedance Tomography enabled by 3D multi-plane softening bioelectronics
通过 3D 多平面软化生物电子学实现快速神经电阻抗断层扫描,增强多束周围神经复合动作电位的定量成像
- 批准号:
10467225 - 财政年份:2018
- 资助金额:
$ 29.88万 - 项目类别:
Fast high-resolution deep photoacoustic tomography of action potentials in brains
大脑动作电位的快速高分辨率深度光声断层扫描
- 批准号:
9423398 - 财政年份:2017
- 资助金额:
$ 29.88万 - 项目类别:
NeuroGrid: a scalable system for large-scale recording of action potentials from the brain surface
NeuroGrid:用于大规模记录大脑表面动作电位的可扩展系统
- 批准号:
9357409 - 财政年份:2016
- 资助金额:
$ 29.88万 - 项目类别:
Noval regulatory mechanisms of axonal action potentials
轴突动作电位的新调节机制
- 批准号:
16K07006 - 财政年份:2016
- 资助金额:
$ 29.88万 - 项目类别:
Grant-in-Aid for Scientific Research (C)