Abstract
Recent advances in viral vector engineering, as well as an increased understanding of the cellular and molecular mechanism of retinal diseases, have led to the development of novel gene therapy approaches. Furthermore, ease of accessibility and ocular immune privilege makes the retina an ideal target for gene therapies. In this study, the nuclear hormone receptor gene Nr2e3 was evaluated for efficacy as broad-spectrum therapy to attenuate early to intermediate stages of retinal degeneration in five unique mouse models of retinitis pigmentosa (RP). RP is a group of heterogenic inherited retinal diseases associated with over 150 gene mutations, affecting over 1.5 million individuals worldwide. RP varies in age of onset, severity, and rate of progression. In addition, ~40% of RP patients cannot be genetically diagnosed, confounding the ability to develop personalized RP therapies. Remarkably, Nr2e3 administered therapy resulted in reduced retinal degeneration as observed by increase in photoreceptor cells, improved electroretinogram, and a dramatic molecular reset of key transcription factors and associated gene networks. These therapeutic effects improved retinal homeostasis in diseased tissue. Results of this study provide evidence that Nr2e3 can serve as a broad-spectrum therapy to treat multiple forms of RP.
Highlights
Recent studies have demonstrated the potential of gene therapy to attenuate or slow the progression of previously untreatable inherited diseases [1]
This study demonstrates a novel approach to gene therapy and suggests that Nr2e3 can potentially serve as a broadspectrum gene therapy to attenuate retinal degeneration
C57BL6/J (B6) animals were treated with AAV8-Nr2e3GFP fusion protein to evaluate any potential detrimental effects of overexpression of Nr2e3, as well as the timing of construct expression post delivery
Summary
Recent studies have demonstrated the potential of gene therapy to attenuate or slow the progression of previously untreatable inherited diseases [1]. There are several ongoing clinical gene augmentation trials for other rare inherited retinal diseases [10,11,12,13]. Several factors such as gene size, gene function, and the large number (~40%) of retinitis pigmentosa (RP) patients that cannot be genetically diagnosed present challenges for developing individual gene replacement/augmentation-based therapies. This study evaluates a unique approach using the nuclear hormone receptor (NHR) gene Nr2e3 as a genetic modifier and therapeutic agent to treat multiple retinal degenerative diseases. ONL degeneration begins at P30, with complete photoreceptor loss by P90 Apparent degeneration can be seen at P14, with a complete ONL degeneration by P60 ONL degeneration is observed at P21, with pigment patches seen at P14 and vessels at P30 Complete vision loss and ONL degenerated by P21
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