Sujun Li, Shyamtanu Datta, Emily Brabbit, Zoe Love, Victoria Woytowicz, Kyle Flattery, Jessica Capri, Katie Yao, Siqi Wu, Michael Imboden, Arun Upadhyay, Rasappa Arumugham, Wallace B. Thoreson, Margaret M. DeAngelis, Neena B. Haider | Gene Therapy | 02 March 2020 | Vol 28 | pgs. 223–241 | doi.org/10.1038/s41434-020-0134-z
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.
Introduction
Recent studies have demonstrated the potential of gene therapy to attenuate or slow the progression of previously untreatable inherited diseases [1]. Gene therapy has evolved from concept to clinic for various genetic disorders including hematological [2], immunological [3], ocular [4, 5], neurodegenerative [6], and metabolic disorders [7]. Due to its ease of accessibility and immune privilege, the eye holds potential as an ideal organ for gene therapy. The most widely accepted success of adeno-associated virus (AAV) vector-mediated ocular gene replacement is for treatment of Leber’s congenital amaurosis 2 (LCA2), a rare retinal disease due to mutations in the RPE65 gene [8, 9]. Currently, there are several ongoing clinical gene augmentation trials for other rare inherited retinal diseases [10,11,12,13]. However, several factors such as gene size, gene function, and the large number (~40%) of retinitis pigmentosa (RP) patients that cannot be genetically diagnosed present challenges for developing individual gene replacement/augmentation-based therapies. Thus, new therapeutic approaches are needed to circumvent these limitations. This study evaluates a unique approach using the nuclear hormone receptor (NHR) gene Nr2e3 as a genetic modifier and therapeutic agent to treat multiple retinal degenerative diseases. Results of this study demonstrate the power of a single genetic modifier in treating retinal diseases.
RP represents a group of inherited diseases, affecting an estimated 1 in 4000 individuals, that cause degeneration of rod and cone photoreceptor cells, leading to the severe vision loss [14, 15]. RP can be inherited through multiple modes of inheritance such as autosomal dominant (30–40% of cases), autosomal recessive (50–60% of cases), or X-linked (5–15% of cases) manner in syndromic or nonsyndromic forms [16,17,18]. Over 150 unique gene mutations have been associated with RP, making it highly heterogenic, with high variability in disease onset, severity, and progression [19,20,21,22,23].
Genetic modifiers are defined as allelic variants found within the normal population [24, 25]. Modifier genes can significantly affect disease outcomes, impacting onset, rate of progression, and severity [24, 26, 27]. Genetic modifier genes are powerful modulators that can enhance or suppress disease phenotypes [24, 27,28,29]. The direct impact of genetic modifiers has been studied extensively in several diseases including cystic fibrosis, epileptic encephalopathy, spinocerebellar ataxia type 1, spinal muscular atrophy, dystonia, and retinal degeneration where drastically altered phenotypes occur when genetic background is shifted [30,31,32,33,34,35,36,37,38]. Haider et al. discovered that shifting the rd7 mutation, a recessive mutation in NHR 2 family e, member 3, Nr2e3 that results in slow progressive retinal degeneration, onto three different genetic backgrounds resulted in complete suppression of the rd7 phenotype in all strains evaluated, and genetic mapping revealed that several modifier genes could independently account for this suppression [39]. The NHR 1 family d, member 1 (Nr1d1), a NHR gene, and cofactor of Nr2e3, was identified as one of the genetic modifiers that can ameliorate Nr2e3 associated retinal degeneration [40].
Mutations in human NR2E3 are associated with several forms of retinal degeneration that vary in phenotype and were categorized by their clinical diagnosis as they were discovered. These clinical categories include the recessive diseases enhanced S-cone syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD) [41,42,43]. NR2E3 mutations are also associated with up to 1% of all autosomal dominant retinitis pigmentosa (adRP) [44, 45]. The association of NR2E3 with several clinical phenotypes and varying modes of inheritance strongly indicates that these retinal diseases manifest on a permissive or selective genetic background and are influenced, at least in part, by genetic modifier genes [46,47,48,49]. Given the role of NHRs such as NR2E3, to modulate numerous key biological networks essential for maintaining retinal homeostasis, this study evaluated Nr2e3 as a broad-spectrum genetic modifier with the potential to attenuate retinal degeneration in several different mouse models.
In this study, the efficacy of subretinal delivery of AAV8-Nr2e3 to attenuate and ameliorate retinal degeneration was assessed in five independent RP models that represent the heterogeneity observed in human RP disease. The five RP models tested were FVB-Pde6ß rd1/NJ (rd1), Rhodopsin null allele (Rho−/−), B6.129S6(Cg)-Rhotm1.1Kpal/J (RhoP23H), BXD24/TyJ-Cep290rd16/J (rd16) and Nr2e3rd7/J (rd7) (Table 1). The rd1 mouse, representing the most severe and early form of human retinal degeneration, harbors a mutant Pde6b gene mapped on chromosome 5 [50,51,52,53,54,55]. The mutant Pde6b gene contains a murine leukemia provirus insertion in intron 1 and a point mutation, which introduces a stop codon in exon 7 (Y347STOP) [56, 57]. Independent of this, a second mutation has been found in this gene, which is the integration of a murine leukemia virus in the first intron of the 6beta (Pde6ß) gene [58]. Mutations in human PDE6ß are associated with RP and autosomal dominant congenital stationary night blindness in humans [59,60,61].
The rhodopsin null (Rho−/−) and the dominant negative RhoP23H alleles both lack a functional rhodopsin gene [62, 63]. Rho−/− mice lack expression of rhodopsin mRNA and protein [64]. In contrast, RhoP23H mice are functional nulls with an amino acid substitution of proline to histidine at position 23 that generate an aberrant message leading to protein misfolding and degradation [63]. Specifically, RhoP23H protein undergoes incomplete glycosylation and is retained in the endoplasmic reticulum (ER) and/or Golgi apparatus where it is degraded [63]. Mutations in the human rhodopsin gene account for the largest portion of inherited retinal degenerations of known genetic etiology [65]. Further, the RhoP23H mutation in particular is one of the most commonly known causes of adRP in humans [63].
The Cep290rd16 (rd16) mouse harbors a mutation in the centrosomal protein Cep290 that results in early-onset retinal degeneration with autosomal recessive inheritance [66]. Mutations in human CEP290 are associated with several syndromic and nonsyndromic forms of retinal degeneration [66, 67]. The rd7 mouse is a model for Nr2e3 associated retinal degenerations. rd7 mice, harboring a recessive mutation in Nr2e3, are clinically characterized by pan retinal spots apparent at eye opening (postnatal (P) day 14), and whorls and rosettes in the outer nuclear layer (ONL) observed histologically by P10 [68, 69]. rd7 mice have two distinct outcomes: a disruption in development of cone cells causing a significant increase of blue opsin expressing cone cells, and progressive degeneration of rod and cone photoreceptor cells [68, 70]. Results of this study show that the administration of AAV8-Nr2e3 therapy improves clinical, histological, functional, and molecular disease outcomes in each of the five models of retinal disease. These studies demonstrate the mechanism of Nr2e3 therapy involves resetting key retinal transcription factors and key biological networks that work in concert with Nr2e3 to modulate the homeostatic state of the retina. This research is predicated on the fact that disease outcome is rarely due to a single gene mutation; rather, it is a result of the combinatorial mutational load on the biological system, which is often strongly influenced by other factors such as modifier genes. This study demonstrates a novel approach to gene therapy and suggests that Nr2e3 can potentially serve as a broad-spectrum gene therapy to attenuate retinal degeneration.
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