Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa

• Published in: Gene therapy 2021-05, Vol.28 (5), p.223-241
• Main Authors: Li, Sujun, Datta, Shyamtanu, Brabbit, Emily, Love, Zoe, Woytowicz, Victoria, Flattery, Kyle, Capri, Jessica, Yao, Katie, Wu, Siqi, Imboden, Michael, Upadhyay, Arun, Arumugham, Rasappa, Thoreson, Wallace B., DeAngelis, Margaret M., Haider, Neena B.
• Format: Article
• Language: English
• Subjects: 14/1; 38/77; 42; 42/44; 631/154/51/201; 631/208/200; 631/337/572; 64/60; 82/51; Analysis; Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Disease Models, Animal; Gene Expression; Gene Therapy; Homeostasis; Human Genetics; Humans; Immune privilege; Mice; Nanotechnology; Orphan Nuclear Receptors; Photoreceptor Cells; Retina; Retinal degeneration; Retinal Degeneration - genetics; Retinal Degeneration - therapy; Retinitis; Retinitis pigmentosa; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - therapy; Transcription factors
• ISSN: 0969-7128; 1476-5462; 1476-5462
• DOI: 10.1038/s41434-020-0134-z

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.