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

点击翻译按钮获取中文摘要

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.