Interspecies Correlations between Human and Mouse NR2E3-Associated Recessive Disease

Abstract

NR2E3-associated recessive disease in humans is historically defined by congenital night blinding retinopathy, characterized by an initial increase in short-wavelength (S)-cone sensitivity and progressive loss of rod and cone function. The retinal degeneration 7 (rd7) murine model, harboring a recessive mutation in the mouse ortholog of NR2E3, has been a well-studied disease model and recently evaluated as a therapeutic model for NR2E3-associated retinal degenerations. This study aims to draw parallels between human and mouse NR2E3-related disease through examination of spectral domain optical coherence tomography (SD-OCT) imaging between different stage of human disease and its murine counterpart. We propose that SD-OCT is a useful non-invasive diagnostic tool to compare human clinical dystrophy presentation with that of the rd7 mouse and make inference that may be of therapeutically relevance. Additionally, a longitudinal assessment of rd7 disease progression, utilizing available clinical data from our patients as well as extensive retrospective analysis of visual acuity data from published cases of human NR2E3-related disease, was curated to identify further valuable correlates between human and mouse Nr2e3 disease. Results of this study validate the slow progression of NR2E3-associated disease in humans and the rd7 mice and identify SD-OCT characteristics in patients at or near the vascular arcades that correlate well with the whorls and rosettes that are seen also in the rd7 mouse and point to imaging features that appear to be associated with better preserved S-cone mediated retinal function. The correlation of histological findings between rd7 mice and human imaging provides a solid foundation for diagnostic use of pathophysiological and prognostic information to further define characteristics and a relevant timeline for therapeutic intervention in the field of NR2E3-associated retinopathies.

In vivo analysis of onset and progression of retinal degeneration in the Nr2e3rd7/rd7 mouse model of enhanced S-cone sensitivity syndrome

“…Initial microglia migration towards ‘rosettes’ is followed by monocyte/macrophage immigration. These findings further illustrate the validity of the Nr2e3 rd7/rd7 mouse retina to study ESCS-associated disease mechanisms 36 .…”

Disease-causing mutations in genes encoding transcription factors critical for photoreceptor development

“…In-depth analysis of ERG and phenotypic findings with ESCS patients at various disease stages suggests a parallel pattern between disease manifestations and observations in rd7 mice ( Wright et al, 2004b ; Iannaccone et al, 2021 ). However, differences between human patients and rd7 mice are noteworthy.…”

Gene-agnostic approaches to treating inherited retinal degenerations

“…There is growing clinical interest across many disciplines in the management of oxidative stress to restore cellular homeostasis ( Ferrante et al, 1997 ; Gilgun-Sherki et al, 2001 ; Ildefonso et al, 2016 ; Pinilla et al, 2022 ). Several clinical trials for retinal supplements ( i.e., vitamin A, lutein, zeaxanthin, docosahexaenoic acid) have explored their capacity to slow the progression of retinitis pigmentosa (RP) ( Iannaccone et al, 2021a ). These initial trials paved the way to continued clinical interest across many disciplines in the management of oxidative stress to restore cellular homeostasis in IRDs ( Ildefonso et al, 2016 ; Pinilla et al, 2022 ).…”

“…Nuclear hormone receptor enhancement ( Figure 2B ) is another potential strategy for preserving visual function in IRDs. Mutations in the human nuclear hormone receptor gene NR2E3 ( Haider et al, 2000 ) with two rather different conditions, a recessive one due to insufficient NR2E3, resulting in a disorder of photoreceptor cell fate known as the Enhanced S-Cone Syndrome (ESCS) in which rods are replaced by S-cones that remain preserved for extended periods of time ( Roman et al, 2019 ; Iannaccone et al, 2021a ) , and in a dominant disorder in which abnormal gain of function mutations cause instead a form of RP without enhanced function or selective preservation of the S-cones (S. Li et al, 2021a ). In the rd7 mouse model, which lacks Nr2e3 and we have shown that faithfully replicated human ESCS ( Roman et al, 2019 ; Batabyal and Kim, 2021 ), augmenting expression of the nuclear hormone receptor NR1D1 led to histological and molecular restoration of the rd7 retina ( Cruz et al, 2014 ).…”