A two-pronged approach to generating novel models of photoreceptor degeneration for regenerative cell therapy
一种双管齐下的方法来生成用于再生细胞治疗的光感受器变性的新模型
基本信息
- 批准号:10685310
- 负责人:
- 金额:$ 96.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-30 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcuteAddressAllelesBiological ModelsCell TherapyClinicDiseaseDisease ProgressionElectroretinographyEvaluationEyeGene ModifiedGenerationsGenesGenetic ModelsGoalsHistologicHomologous GeneHumanInheritedLaser injuryLasersLeber&aposs amaurosisModelingMonitorNatural regenerationNatureOpticsOrganismPathologicPatientsPhenotypePhotoreceptorsPlatinumReportingRetinaRetinal DegenerationRetinal DiseasesRetinitis PigmentosaRodSpecificityTechnologyTestingTherapeuticTimeTranslationsTransplantationVertebrate PhotoreceptorsVisual SystemVisual impairmentautosomecausal variantcell preparationcell replacement therapyearly onsetfunctional restorationfundus imaginggenome editinghuman embryonic stem cellin vivo imaginginduced pluripotent stem cellmutantnovelphotoreceptor degenerationregenerative cellretinal progenitor celltomographytranscription activator-like effector nucleases
项目摘要
PROJECT SUMMARY
Inherited retinal diseases (IRD), such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), are a common cause of visual impairment worldwide. Recent studies show that cell replacement therapy is a promising therapeutic option for IRD patients with severe retinal degeneration that destroys photoreceptors. We and others recently reported long-term survival and integration of human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) derived retinas in a novel laser-induced photoreceptor degeneration model. While the laser ablation model can be generated rapidly as an acute degeneration model, it does not have the progressive pathophysiological nature (e.g., disease time course, retinal remodeling, etc.) of IRD. To address this issue, we developed a highly efficient genome-editing technology, Platinum Talen, which leads to gene disruption in multiple organisms with high efficacy and specificity. By applying Platinum Talen to this novel model, we achieved one-step generation of biallelic gene modifications with high efficiency (40-50%) in preliminary studies. Since substantial information regarding the survival and integration of transplanted photoreceptor cells or retinal sheets have been obtained in laser injury models, we propose a two-pronged strategy to generating novel translation-enabling models to evaluate survival and integration of regenerated photoreceptors in the visual system: 1) to use laser-induced photoreceptor degeneration model; 2) one-step generation of biallelic mutants by Platinum Talen. We will then systematically compare the survival and integration of regenerated photoreceptors in the two model systems. Aim 1 will generate novel models of photoreceptor degeneration by laser ablation and Platinum Talen. Aim 2 will perform comprehensive ophthalmic phenotyping of laser-induced and Talen-edited models of photoreceptor degeneration. Aim 3 will evaluate survival and integration of human induced pluripotent stem cell (hiPSC)-derived retina sheets in the two models of photoreceptor degeneration.
项目摘要
遗传性视网膜疾病(Inherited retinal diseases,IRD),如视网膜色素变性(retinitis pigmentosa,RP)、莱伯先天性黑蒙(Leber congenital amaurosis,LCA),是世界范围内视力损害的常见原因。最近的研究表明,细胞替代疗法是一个有前途的治疗选择,IRD患者严重视网膜变性,破坏光感受器。我们和其他人最近报道了人胚胎干细胞(hESC)或人诱导多能干细胞(hiPSC)衍生的视网膜在新型激光诱导的光感受器变性模型中的长期存活和整合。虽然激光消融模型可以作为急性变性模型快速生成,但它不具有进行性病理生理学性质(例如,疾病时间进程、视网膜重塑等)的IRD。为了解决这个问题,我们开发了一种高效的基因组编辑技术Platinum Talen,它可以在多种生物体中以高效率和特异性破坏基因。通过将Platinum Talen应用于该新模型,我们在初步研究中以高效率(40-50%)实现了双等位基因修饰的一步生成。由于在激光损伤模型中已经获得了关于移植的感光细胞或视网膜片的存活和整合的大量信息,因此我们提出了一种双管齐下的策略来产生新的抑制模型以评估再生的感光细胞在视觉系统中的存活和整合:1)使用激光诱导的感光细胞变性模型; 2)由Platinum Talen一步产生双等位基因突变体。然后,我们将系统地比较两个模型系统中再生光感受器的存活和整合。目的1将通过激光消融和Platinum Talen产生新的光感受器变性模型。目的2将对激光诱导和Talen编辑的感光细胞变性模型进行全面的眼科表型分析。目的3将评估人诱导多能干细胞(hiPSC)衍生的视网膜片在两种感光细胞变性模型中的存活和整合。
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)
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Yingbin Fu其他文献
Yingbin Fu的其他文献
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{{ truncateString('Yingbin Fu', 18)}}的其他基金
Mechanistic study and therapeutic application of AIBP in AMD
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- 批准号:
10733843 - 财政年份:2023
- 资助金额:
$ 96.05万 - 项目类别:
A two-pronged approach to generating novel models of photoreceptor degeneration for regenerative cell therapy
一种双管齐下的方法来生成用于再生细胞治疗的光感受器变性的新模型
- 批准号:
10329873 - 财政年份:2021
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$ 96.05万 - 项目类别:
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Mechanisms and treatment strategies for polypoidal choroidal vasculopath
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8628340 - 财政年份:2014
- 资助金额:
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