Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa.

Spencer M. Moore,Daniel L. Chao,Dorota Skowronska-Krawczyk

doi:10.3390/jcm9072224

Spencer M. Moore, Daniel L. Chao + Show 1 more

Open Access

https://doi.org/10.3390/jcm9072224

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Abstract

Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) with a prevalence of 1:4000, characterized by initial rod photoreceptor loss and subsequent cone photoreceptor loss with accompanying nyctalopia, visual field deficits, and visual acuity loss. A diversity of causative mutations have been described with autosomal dominant, autosomal recessive, and X-linked inheritance and sporadic mutations. The diversity of mutations makes gene therapy challenging, highlighting the need for mutation-agnostic treatments. Neural leucine zipper (NRL) and NR2E3 are factors important for rod photoreceptor cell differentiation and homeostasis. Germline mutations in NRL or NR2E3 leads to a loss of rods and an increased number of cones with short wavelength opsin in both rodents and humans. Multiple groups have demonstrated that inhibition of NRL or NR2E3 activity in the mature retina could endow rods with certain properties of cones, which prevents cell death in multiple rodent RP models with diverse mutations. In this review, we summarize the literature on NRL and NR2E3, therapeutic strategies of NRL/NR2E3 modulation in preclinical RP models, as well as future directions of research. In summary, inhibition of the NRL/NR2E3 pathway represents an intriguing mutation agnostic and disease-modifying target for the treatment of RP.

Highlights

In Retinitis pigmentosa (RP), there is a progressive loss of rod photoreceptors, which is followed by a secondary cone photoreceptor degeneration, at which point patients experience decreased central visual acuity
Nearly 100 unique genes have been implicated in RP pathogenesis, with significant overlap among genes shared with RP and the related inherited retinal dystrophy (IRD) including Leber’s Congenital Amaurosis (LCA), cone-rod dystrophy, and macular dystrophy [3]
Mutations in the Neural leucine zipper (NRL) and NR2E3 genes encoding rod-specific transcription factors exemplify this diversity, as autosomal dominant [12,13], autosomal recessive [14,15], and sporadic [16] mutations have been implicated in RP and the related IRD, enhanced S-cone syndrome (ESCS)

Summary

Introduction to Retinitis Pigmentosa

Retinitis pigmentosa (RP) encompasses a genetically heterogeneous collection of inherited progressive retinal degenerative disorders affecting approximately 1:4000 individuals [1] in the United States. Among the inherited retinal dystrophies (IRDs), RP is the most common. RP is marked clinically by retinal findings of bone-spicule pigmentary clumping, vascular attenuation, and optic nerve (ON) pallor [3]. Patients usually experience symptoms of nyctalopia and progressive concentric peripheral visual field loss beginning as early as adolescence or young adulthood, with progressive visual decline. In RP, there is a progressive loss of rod photoreceptors, which is followed by a secondary cone photoreceptor degeneration, at which point patients experience decreased central visual acuity. Developing effective treatments for IRDs including RP remains challenging, due to the genetic heterogeneity underlying the disease

Genetic Heterogeneity of Retinitis Pigmentosa

Toward a Mutation-Independent Treatment

Main Text

Human Phenotypes of NRL Pathway Mutations

NRL as a Regulator of Rod Photoreceptor Transcription

NR2E3 Suppresses Cone Transcription

Manipulating the NRL Pathway as a Neuroprotective Strategy in RP

Findings

Manipulating the NR2E3 Pathway as a Neuroprotective Strategy in RP