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| 1 | The future of retinal gene therapy: evolving from subretinal to intravitreal vector delivery显示文摘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 barriers have been developed. This paper reviews ongoing efforts to develop novel, safe and efficacious methods for intravitreal delivery of therapeutic genes for inherited retinal degenerations. To date, the most promising results are achieved in rodents with robust, pan-retinal transduction following intravitreal delivery. Trials in larger animal models demonstrate transduction mostly of inner retinal layers. Despite ongoing efforts, currently no intravitreally-injected vector has demonstrated outer retinal transduction efficacy comparable to that of subretinal delivery. Further work is warranted to test promising new viral and non-viral vectors on large animal models of inherited retinal degenerations. Positive results will pave the way to development of the next generation of treatments for inherited retinal degeneration. | Maya Ross Ron Ofri | 2021 | Neural Regeneration Research2021，16，9： | 2 |
| 2 | Cataract development in diabetic sand rats treated with alpha-lipoic acid and its gamma- linolentic acid conjugate显示文摘 | Borenshtein D Ofri R Werman M | 2001 | Diabetes Metab Res Rev2001，17，： | 1 |
| 3 | Guidelines for clinical electroretinography in the dog 显示文摘 | Narfstrom K Ekesten B Rosolen SG Spiess BM Percicot CL Ofri R | 2002 | Doc Ophthalmol2002，105，2： | 1 |
| 4 | Clinical evaluation of pimecrolimus eye drops for treatment of canine keratoconjuncti- vitis sicca: A comparison with cyclosporine A显示文摘 | Ofri R Lambrou GN Allgoewer I | 2009 | Vet J2009，179，1： | 1 |
| 5 | Development of the refractive state in eyes of ostrich hicks(Struthio camelus)显示文摘 | Ofri R Mil odot R Shimoni R | | 0，，05： | 1 |
| 6 | Inflammatory mediators in breast cancer: Coordinated expression of TNF-α & IL-1α with CCL2 & CCL5 and effects on epithelial-to-mesenchymal transition 显示文摘 | Soria G Ofri - Shahak M Haas I | 2011 | BMC Cancer2011，11，130： | 1 |
| 7 | Cataract development in diabetic sand rats treated with alpha-lipoic acid and its gamma- linolenic acid conjugate显示文摘 | Borenshtein D Ofri R Werman M | 2001 | Diabetes Metab Res Rev2001，17，1： | 1 |
| 8 | Development of the refractive state in eyes of ostrich hicks (Struthio camelus)显示文摘 | Ofri R Millodot R Shimoni R | 2001 | Am J Vet Res2001，62，5： | 1 |
| 9 | Spontaneous cataract resorption in an ostrich 显示文摘 | Ofri R Horowitz I | 1995 | Vet Rec1995，136，11： | 1 |
| 10 | Development of inner retinal function,evidenced by the pattern electroretinogram,in the rat显示文摘 | Ben-Shlomo G Ofri R | | 0，，： | 1 |
| 11 | Cataract development in diabetic sand rats treated with alpha-lipoic acid and its gamma- linolenic acid conjugate 显示文摘 | Borenshtein D Ofri R Werman M | 2001 | Diabetes Metab Res Rev2001，17，1： | 1 |
| 12 | Intraocular pressure and glaucoma显示文摘 | OFRI R | 2002 | Vet Clin North Am Exot Anim Pract2002，5，2： | 1 |
| 13 | Active control for large space structure by fuzzy logic controllers 显示文摘 | Ofri A Tanchum W Guterman H | 1996 | Electrical & Electronics Engineers in Israel1996，，： | 1 |
| 14 | Functional and structural evaluation of lamotrigine treatment in rat models of acute and chronic ocular hypertension显示文摘 | Shai Sandalon Birte K?nnecke Hani Levkovitch-Verbin Mikael Simons Katharina Hein Muriel B. S?ttler Mathias B?hr Ron Ofri | 2013 | Experimental Eye Research2013，，： | 1 |
| 15 | Light at the end of the tunnel? Advances in the understanding and treatment of glaucoma and inherited retinal degeneration 显示文摘 | Ofri R Narfstrom K | 2007 | Vet J2007，174，1： | 1 |
| 16 | Modern and fos- sil charcoal: aspects of structure and diagenesis 显示文摘 | Cohen - Ofri I Weiner L Boaretto E | 2006 | Journal of Archaeological Science2006，33，3： | 1 |
| 17 | Clinical evaluation of pirnecrolimus eye drops for treatment of canine keratoconjunctivitis sicca: A comparison with cyclosporine A 显示文摘 | Ofri R Lambrou G N Allgoewer I | 2009 | Vet J2009，179，1： | 1 |
| 18 | Riding the rails-different modes for RNA complex transport in axons显示文摘Neurons are highly polarized cells with axons that innervate distant targets.The distance of subcellular compartments from the nucleus requires sophisticated transport mechanisms and local action of vital processes for proper function and rapid responses to local stimuli(Terenzio et al.,2017).This is partially achieved by transport of mRNAs to subcellular locations and regulation of local translation for axonal growth,branching,synaptic plasticity,and regeneration,among other needs.Axonally synthesized proteins support neuronal survival,and axonal development,maintenance,and growth(Rishal and Fainzilber,2014;Dalla Costa et al.,2021).Thus,understanding the mechanisms that promote RNA transport to subcellular locations in neurons will contribute to the development of novel strategies to enhance axon regeneration and survival. | Ofri Abraham Mike Fainzilber | 2022 | Neural Regeneration Research2022，17，12： | 0 |
| 19 | 电商做不好?你要构建全景图显示文摘近几年,电子商务在中国发展迅速,已经是大势所趋,许多企业在电商大潮下,也顺势而为,建立起自己的电子商务业务。但对大多数企业来说,涉足电商是一个全新的命题,面临的困难和挑战也可想而知。 | Ofri Cohen | 2016 | 成功营销2016，0，1： | 0 |
| 20 | 甲流疫苗与“情绪流行病学”显示文摘记录下情绪流行病学和疾病流行病学,并且以同等的紧迫性对二者进行治疗,是当前流感季节的基本临床工具。2009年春天,当甲型H1N1流感首次受到关注时,我的病人们陷入了恐慌。我们的诊所不断接到电话以及来访的病人,他们部问了同一个问题:“什么时候会有疫苗?” | Danielle Ofri 戴廉 | 2009 | 中国医院院长2009，5，24： | 0 |
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