Retinal Gene Distribution and Functionality Implicated in Inherited Retinal Degenerations Can Reveal Disease-Relevant Pathways for Pharmacologic Intervention.

Debarshi Mustafi,Krzysztof Palczewski,Amirmohsen Arbabi,Hossein Ameri

doi:10.3390/ph12020074

Abstract

The advent of genetic therapies for inherited retinal diseases (IRDs) has spurred the need for precise diagnosis and understanding of pathways for therapeutic targeting. The majority of IRDs that are clinically diagnosed, however, lack an identifiable mutation in established disease-causing loci and thus can be investigated with limited rational drug discovery methods. Transcriptome profiling of the retina can reveal the functional state of the tissue, and geographic profiling can uncover the various clinical phenotypic presentations of IRDs and aid in pharmaceutical intervention. In this investigation, we detail the retinal geographic expression of known retinal disease-causing genes in the primate retina and functional targetable pathways in specific IRDs. Understanding the genetic basis as well as the resulting functional consequences will assist in the discovery of future therapeutic interventions and provide novel insights to medicinal chemists. Herein, we report that, despite the genetic heterogeneity of retinal diseases, potential functional pathways can be elucidated for therapeutic targeting and be used for predictive phenotypic and genotypic modeling of novel IRD presentations.

Highlights

Inherited retinal degenerations (IRDs) are predominantly monogenic [1], with a prevalence of ~1 in 3000 individuals [2]
Healthy primate M. fascicularis were chosen for the study to prevent any confounders of aging or disease in the elucidation of the physiologic genetic landscape of the primate retina
As previously shown [15], of the 807 genes that were differentially expressed by at least twofold (p value ≤ 0.05), 499 genes were more highly expressed in the central retina, and 308 genes were more highly expressed in the peripheral retina, highlighting the key genetic frameworks instrumental in the function and maintenance of the adult primate retina

Summary

Introduction

Inherited retinal degenerations (IRDs) are predominantly monogenic [1], with a prevalence of ~1 in 3000 individuals [2]. Diagnosis still remains difficult because of the genetic heterogeneity of retinal dystrophies [4], and this lack of identifiable disease pathways has limited medicinal approaches to drug discovery. Retinitis pigmentosa (RP) is the most common IRD, with over 3000 genetic mutations in approximately 70 genes [5], yet less than 60% of patients have an identifiable mutation in these established disease-causing loci [6], thereby highlighting the need for the discovery of novel loci in monogenic retinal dystrophies [7] for therapeutic targeting. In the case of multifactorial retinal degenerations, even less is known, as multi-genic inheritance patterns and genetic modifiers [8] have confounded molecular diagnosis. Whereas monogenic and multigenic forms of retinal degeneration are distinct, the predominant driving force behind them is a dysfunction at the level of the photoreceptor and the neighboring retinal pigment epithelium (RPE) [9]

Methods

Results

Conclusion