Novel bioreducible polymer-based delivery platform for intravitreal gene transfer to retina

用于玻璃体内基因转移至视网膜的新型生物可还原聚合物递送平台

基本信息

批准号：
10573812
负责人：
Jung Soo Suk
金额：
$ 44.28万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2025-09-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573812
关键词：
Address Adhesives Adverse effects Amines Back Blindness Cattle Cells Charge Chemicals Clinical Data Dependovirus Disulfides Dose Economic Burden Endosomes Endowment Engineered Gene Engineering Environment Exhibits Eye Eye diseases FDA approved Formulation Gel Gene Delivery Gene Transfer Genes Goals Immune response In Vitro Inflammation Inherited Injections Inner Limiting Membrane Kinetics Lead Link Mediating Modeling Mus Names Nature Nuclear Nucleic Acids Occupations Operative Surgical Procedures Outcome Pathologic Patients Penetration Photoreceptors Plasmids Polyethylene Glycols Polymers Procedures Reporter Reporting Retina Retinal Diseases Retinal Ganglion Cells Retinal gene therapy Risk Route Safety Side Site Synthetic Genes Testing Therapeutic Transfection Trauma Tropism Variant Viral Vector Virus Visual impairment adeno-associated viral vector clinical investigation clinically relevant cost cost effective delivery vehicle design disulfide bond extracellular gene delivery system gene therapy human pluripotent stem cell immunogenicity improved in vivo lead candidate monomer nanoparticle nanoparticle delivery non-viral gene delivery novel nucleic acid-based therapeutics optic nerve disorder promoter prototype screening subretinal injection surface coating therapeutic transgene trafficking transgene expression uptake vector

项目摘要

PROJECT SUMMARY Our primary goal in this proposal is to develop a polymer-based synthetic gene delivery platform for gene therapy of acquired and/or inherited retinal and optic nerve disorders. Viral vectors, particularly adeno-associated virus (AAV), have been the gene delivery vector of choice to date but several inherent shortcomings necessitate an alternative that can accommodate the ever-increasingly need for novel gene therapy products. These include limited packaging capacity, vector-specific immune responses, and extremely high cost. In addition, subretinal injection, despite being widely practiced and affording direct access to the outer retinal layer, poses several drawbacks such as photoreceptor trauma and limited topographic therapeutic coverage. To this end, we propose to develop and evaluate novel environmentally-sensitive polymer-based gene delivery nanoparticles (NPs) for intravitreal gene delivery to the retina for broad retinal gene therapy applications while avoiding the above- mentioned limitations. Specifically, our platform will be designed to overcome key extracellular barriers, including the vitreous gel and inner limiting membrane, to enable widespread retinal gene transfer, and to promote endosomal escape and intracellular release of therapeutic nucleic acid payloads for enhanced transfection of retinal cells. Importantly, non-immunogenic nature of our platform will allow multiple administrations to amplify the level of transgene expression, potentially matching or surpassing the efficacy achievable by clinically validated viral vectors. Of note, although non-viral gene delivery systems do not readily exhibit a specific cell tropism, cell-specific therapeutic transgene expression can be achieved with the use of cell-specific promoters if desired. Synthetic gene delivery systems that provide extensive and safe transgene expression in retina can be of broad clinical utility.

项目概要我们在该提案中的主要目标是开发用于基因治疗的基于聚合物的合成基因递送平台获得性和/或遗传性视网膜和视神经疾病。病毒载体，特别是腺相关病毒 (AAV)，迄今为止已成为选择的基因传递载体，但其一些固有的缺点需要可以满足对新型基因治疗产品不断增长的需求的替代方案。这些包括有限的包装容量、载体特异性免疫反应以及极高的成本。此外，视网膜下尽管注射已被广泛应用并可直接进入视网膜外层，但仍存在一些问题缺点如感光器创伤和有限的地形治疗覆盖范围。为此，我们建议开发和评估新型环境敏感聚合物基基因传递纳米颗粒（NP）玻璃体内基因递送至视网膜，用于广泛的视网膜基因治疗应用，同时避免上述情况提到的限制。具体来说，我们的平台将旨在克服关键的细胞外障碍，包括玻璃体凝胶和内界膜，以实现广泛的视网膜基因转移，并促进治疗性核酸有效负载的内体逃逸和细胞内释放，以增强转染视网膜细胞。重要的是，我们平台的非免疫原性将允许多次给药来放大转基因表达水平，可能匹配或超过临床可达到的功效经过验证的病毒载体。值得注意的是，尽管非病毒基因传递系统不容易表现出特定的细胞如果使用细胞特异性启动子，可以实现向性、细胞特异性治疗性转基因表达想要的。在视网膜中提供广泛且安全的转基因表达的合成基因递送系统可以是具有广泛的临床实用性。