학술논문
AAV2 vector optimization for retinal ganglion cell-targeted delivery of therapeutic genes.
Document Type
Academic Journal
Author
Chaqour B; Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA.; F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Duong TT; Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA.; F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; GlaxoSmithKline, Collegeville, PA, 19426, USA.; Yue J; Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA.; F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Liu T; Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA.; F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Spark Therapeutics, Philadelphia, PA, 19104, USA.; Camacho D; Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA.; F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Dine KE; Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA.; F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Esteve-Rudd J; Gyroscope Therapeutics Limited, a Novartis Company, London, N7 9AS, UK.; Ellis S; Gyroscope Therapeutics Limited, a Novartis Company, London, N7 9AS, UK.; Bennett J; Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA.; F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.; Shindler KS; Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA. kenneth.shindler@pennmedicine.upenn.edu.; F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. kenneth.shindler@pennmedicine.upenn.edu.; Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA. kenneth.shindler@pennmedicine.upenn.edu.; Ross AG; Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, 19104, USA. ahmara.ross@pennmedicine.upenn.edu.; F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. ahmara.ross@pennmedicine.upenn.edu.; Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA. ahmara.ross@pennmedicine.upenn.edu.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9421525 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5462 (Electronic) Linking ISSN: 09697128 NLM ISO Abbreviation: Gene Ther Subsets: MEDLINE
Subject
Language
English
Abstract
Recombinant adeno-associated virus (AAV)-2 has significant potential as a delivery vehicle of therapeutic genes to retinal ganglion cells (RGCs), which are key interventional targets in optic neuropathies. Here we show that when injected intravitreally, AAV2 engineered with a reporter gene driven by cytomegalovirus (CMV) enhancer and chicken β-actin (CBA) promoters, displays ubiquitous and high RGC expression, similar to its synthetic derivative AAV8BP2. A novel AAV2 vector combining the promoter of the human RGC-selective γ-synuclein (hSNCG) gene and woodchuck hepatitis post-transcriptional regulatory element (WPRE) inserted upstream and downstream of a reporter gene, respectively, induces widespread transduction and strong transgene expression in RGCs. High transduction efficiency and selectivity to RGCs is further achieved by incorporating in the vector backbone a leading CMV enhancer and an SV40 intron at the 5' and 3' ends, respectively, of the reporter gene. As a delivery vehicle of hSIRT1, a 2.2-kb therapeutic gene with anti-apoptotic, anti-inflammatory and anti-oxidative stress properties, this recombinant vector displayed improved transduction efficiency, a strong, widespread and selective RGC expression of hSIRT1, and increased RGC survival following optic nerve crush. Thus, AAV2 vector carrying hSNCG promoter with additional regulatory sequences may offer strong potential for enhanced effects of candidate gene therapies targeting RGCs.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)