| Autor: |
Hughes CP; Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, UK., O'Flynn NMJ; Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, UK., Gatherer M; Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, UK., McClements ME; Oxford Eye Hospital and Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK., Scott JA; Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, UK., MacLaren RE; Oxford Eye Hospital and Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK., Goverdhan S; Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, UK., Glennie MJ; Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Lotery AJ; Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, UK. |
| Abstrakt: |
While anti-angiogenic therapies for wet age-related macular degeneration (AMD) are effective for many patients, they require multiple injections and are expensive and prone to complications. Gene therapy could be an elegant solution for this problem by providing a long-term source of anti-angiogenic proteins after a single administration. Another potential issue with current therapeutic proteins containing a fragment crystallizable (Fc) domain (such as whole antibodies like bevacizumab) is the induction of an unwanted immune response. In wet AMD, a low level of inflammation is already present, so to avoid exacerbation of disease by the therapeutic protein, we propose single-chain fragment variable (scFv) antibodies, which lack the Fc domain, as a safer alternative. To investigate the feasibility of this, anti-vascular endothelial growth factor (VEGF)-blocking antibodies in two formats were produced and tested in vitro and in vivo . The scFv transgene was then cloned into an adeno-associated virus (AAV) vector. A therapeutic effect in a mouse model of choroidal neovascularization (CNV) was demonstrated with antibodies in both scFv and immunoglobulin G1 (IgG1) formats (p < 0.04). Importantly, the scFv anti-VEGF antibody expressed from an AAV vector also had a significant beneficial effect (p = 0.02), providing valuable preclinical data for future translation to the clinic. |
