Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa
Authors: Margaret M DeAngelis
Emily Brabbit
Wallace B Thoreson
Victoria Woytowicz
Michael Imboden
Rasappa Arumugham
Siqi Wu
Sujun Li
Arun Upadhyay
Neena B Haider
Jessica Capri
Zoe Love
Kyle Flattery
Katie Yao
Shyamtanu Datta
Journal: Gene Therapy (2021)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: viral vector engineering; gene therapy; retinal diseases; Nr2e3; retinitis pigmentosa
Affiliations: Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA., Ocugen Inc., Malvern, PA, USA., Department of Ophthalmology and Visual Sciences, Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA., Moran Eye Center for Translational Medicine, Salt Lake, UT, USA., Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. .

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. 

Retracted: No

PubPeer comments:
 Figure 3 and Figure 11: One panel is duplicated, I ve added the magenta shapes to show where I mean. If I read this correctly, the mice were treated at different times, so these images should be different (as are the rest in these two figures). Would the authors please comment? ![file] , 
 Another potential concern: * Blue boxes: One of the H E stained tissues from Figure 1A (animals injected at PO, tissue collected at P30) appears to overlap with a panel in Figure 11B (animal injected at P21 and evaluated at 2-3 months post injection). Although these are both untreated animals, the time points appear to be different, so these sound like different experiments. Can the authors perhaps clarify, please? ![file] , 
 Another potential problem: * Orange boxes: A panel in Figure 12 (untreated animal) looks very similar to a panel in Figure 1C (P30 affected B6.Cg-Mor7AKR:Nr2e3rd7 rd7 mouse) of Nelly M Cruz et al (2014), PLoS ONE 9(1): e87942. DOI:10.1371 journal.pone.0087942. Could the authors please explain if these are representing the same animals, or if it was appropriate to compare experiments 7 years apart with each other? ![file] A finding by ImageTwin. , 
 Another potential problem - well, two actually: * Yellow boxes: theAAV8 Nr233 treated green Opsin rd7 panel of Figure 5 (P0 injected mice evaluated at day 30) appears to overlap with the AAV8 Nr233 treated green Opsin rd16 panel of Figure 12 (P21 injected mice evaluated at 2-3 months) * Cyan boxes: In Figure 12, the AAV8 Nr233 treated green Opsin Rho P23H panel appears to overlap with the AAV8 Nr233 treated Blue Opsin Rd7 panel ![file] ![file] , 
 Potential concerns about Supplemental Figure 2A. First, the full figure: ![file] * Green ellipses: The distribution of the white dots in the Untreated panel in A looks unexpectedly similar to that of the AAV5-Nr2e3 Treated panel, with some slight rotation and lateral shift. ![file] , 
 Also in Figure 12, after adjusting the contrast and color levels, there is a surprising degree of similarity in the background noise between the two panels highlighted. ![file] ,