The future of retinal gene therapy: evolving from subretinal to intravitreal vector delivery  

作　　者：Maya Ross Ron Ofri 

机构地区：[1]Koret School of Veterinary Medicine,The Hebrew University of Jerusalem,Rehovot,Israel

出　　处：《Neural Regeneration Research》2021年第9期1751-1759,共9页中国神经再生研究（英文版）

基　　金：funded by grants from the Israel Science Foundation(1257/15);the Chief Scientist Office,Ministry of Health(3-15068),awarded to RO。

摘　　要：Inherited retinal degenerations are a leading and untreatbale cause of blindness, and as such they are targets for gene therapy. Numerous gene therapy treatments have progressed from laboratory research to clinical trails, and a pioneering gene therapy received the first ever FDA approval for treating patients. However, currently retinal gene therapy mostly involves subretinal injection of the therapeutic agent, which treats a limited area, entails retinal detachment and other potential complications, and requires general anesthesia with consequent risks, costs and prolonged recovery. Therefore there is great impetus to develop safer, less invasive and cheapter methods of gene delivery. A promising method is intravitreal injection, that does not cause retinal detachment, can lead to pan-retinal transduction and can be performed under local anesthesia in outpatient clinics. Intravitreally-injected vectors face several obstacles. First, the vector is diluted by the vitreous and has to overcome a long diffusion distance to the target cells. Second, the vector is exposed to the host's immune response, risking neutralization by pre-existing antibodies and triggering a stronger immune response to the injection. Third, the vector has to cross the inner limiting membrane which is both a physical and a biological barrier as it contains binding sites that could cause the vector's sequestration. Finally, in the target cell the vector is prone to proteasome degradation before delivering the transgene to the nucleus. Strategies to overcome these obstacles include modifications of the viral capsid, through rational design or directed evolution, which allow resistance to the immune system, enhancement of penetration through the inner limiting membrane or reduced degradation by intracellular proteasomes. Furthermore, physical and chemical manipulations of the inner limiting membrane and vitreous aim to improve vector penetration. Finally, compact non-viral vectors that can overcome the immunological, physical and anatomical and

关 键 词：adeno-associated virus animal model BLINDNESS gene therapy inner limiting membrane PHOTORECEPTORS RETINA retinitis pigmentosa VITREOUS 

分 类 号：R774.1[医药卫生—眼科]