AAV2 is also the serotype in Luxturna, the first ocular AAV gene therapy to obtain regulatory approval in the United States and Europe. AAV2 is the most widely used serotype due to efficient transduction of retinal neurons, superior safety over lentiviral vectors, effective transduction in injured or diabetic eyes, and long-term transgene expression. To date, over 30 AAV clinical trials have commenced for ocular diseases in which most are targeted for monogenic, Mendelian retinal diseases. These factors are key to why AAVs are frequently used in clinical trials in ophthalmology and neurology. They exhibit low immunogenicity and mainly initiate transgene expression by forming episomal DNA in the nucleus of transduced cells. Recombinant adeno-associated viral (AAV) vectors can achieve efficient neuronal transduction in the central nervous system (CNS). Taken together, this promoter comparison study contributes to optimising AAV-mediated transduction in the retina, and could be valuable for research in ocular disorders, particularly those with large or complex genetic cargos. We also found that these promoters could transduce human retina ex vivo, although expression was predominantly in glial cells due to low RGC viability. The ubiquitous CBA, CMV, and sCAG promoters expressed eGFP in a variety of cell types across multiple retinal layers including Müller glia and astrocytes. The PGK promoter had predominant expression in both RGCs and AII amacrine cells. The SYN promoter had almost exclusive transgene expression in RGCs. CBA, CMV, and PGK had moderate expression by comparison. eGFP expression was strongest in the retina, optic nerves and brain when driven by the sCAG and SYN promoters. The promoters driving enhanced green fluorescent protein (eGFP) were examined in adult C57BL/6J mice eyes and tissues of the visual system. This study compares five promoters designed to maximise AAV2 cargo space for gene delivery: chicken β-actin (CBA), cytomegalovirus (CMV), short CMV early enhancer/chicken β-actin/short β-globulin intron (sCAG), mouse phosphoglycerate kinase (PGK), and human synapsin (SYN). Promoters influence the strength and cell-selectivity of transgene expression. The AAV serotype however is not the only factor contributing to the effectiveness of gene therapies. AAV serotype 2 (AAV2) is commonly used to deliver transgenes to retinal ganglion cells (RGCs) via intravitreal injection. Recombinant adeno-associated viral vectors (AAVs) are an effective system for gene transfer.
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