Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

Clérin, Emmanuelle; Marussig, Myriam; Sahel, José‐Alain; Léveillard, Thierry

doi:10.3390/ijms21051625

Cited by 22 publications

(19 citation statements)

References 178 publications

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“…Most forms of RP are due to primary damage of rod cells, which is followed by a secondary loss of cones ( Figure 1C; Sancho-Pelluz et al, 2008). RdCVF is a retina-specific trophic factor that induces cone survival and functional rescue in RP animal models (Leveillard et al, 2004;Yang et al, 2009) by modulating energy metabolism, accelerating glucose entry and enhancing aerobic glycolysis, thus holding good promises as an effective AAV-mediated mutation-independent therapy (Leveillard and Sahel, 2010;Ait-Ali et al, 2015;Byrne et al, 2015;Clerin et al, 2020).…”

Section: Neuroprotection Approachesmentioning

confidence: 99%

Mutation-Independent Therapies for Retinal Diseases: Focus on Gene-Based Approaches

et al. 2020

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Gene therapy is proving to be an effective approach to treat or prevent ocular diseases ensuring a targeted, stable, and regulated introduction of exogenous genetic material with therapeutic action. Retinal diseases can be broadly categorized into two groups, namely monogenic and complex (multifactorial) forms. The high genetic heterogeneity of monogenic forms represents a significant limitation to the application of gene-specific therapeutic strategies for a significant fraction of patients. Therefore, mutation-independent therapeutic strategies, acting on common pathways that underly retinal damage, are gaining interest as complementary/alternative approaches for retinal diseases. This review will provide an overview of mutation-independent strategies that rely on the modulation in the retina of key genes regulating such crucial degenerative pathways. In particular, we will describe how gene-based approaches explore the use of neurotrophic factors, microRNAs (miRNAs), genome editing and optogenetics in order to restore/prolong visual function in both outer and inner retinal diseases. We predict that the exploitation of gene delivery procedures applied to mutation/gene independent approaches may provide the answer to the unmet therapeutic need of a large fraction of patients with genetically heterogeneous and complex retinal diseases.

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Section: Neuroprotection Approachesmentioning

confidence: 99%

Mutation-Independent Therapies for Retinal Diseases: Focus on Gene-Based Approaches

et al. 2020

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“…Viral-mediated expression of RdCVF into mouse models of retinal degeneration showed promising results (Y. Yang et al, 2009;Byrne et al, 2015) with subsequent development of a vector for near future clinical trials (Clerin, Marussig, Sahel, & Leveillard, 2020) (Table 3).…”

Section: Neuroprotective Therapiesmentioning

confidence: 99%

“…RdCVF is believed to stimulate glucose transport via GLUT1 into cone photoreceptors which in turn stimulates aerobic glycolysis and cone survival (Ait‐Ali et al, 2015). Viral‐mediated expression of RdCVF into mouse models of retinal degeneration showed promising results (Y. Yang et al, 2009; Byrne et al, 2015) with subsequent development of a vector for near future clinical trials (Clerin, Marussig, Sahel, & Leveillard, 2020) (Table 3).…”

Section: The Future Of Ocular Gene Therapy: Tackling New Genes With Nmentioning

confidence: 99%

The new landscape of retinal gene therapy

Pennesi

2020

American J of Med Genetics Pt C

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Novel therapeutics for inherited retinal dystrophies (IRDs) have rapidly evolved since groundbreaking clinical trials for LCA due to RPE65 mutations led to the first FDAapproved in vivo gene therapy. Since then, advancements in viral vectors have led to more efficient AAV transduction and developed other viral vectors for gene augmentation therapy of large gene targets. Furthermore, significant developments in gene editing and RNA modulation technologies have introduced novel capabilities for treatment of autosomal dominant diseases, intronic mutations, and/or large genes otherwise unable to be treated with current viral vectors. We highlight strategies currently being evaluated in gene therapy clinical trials and promising preclinical developments for IRDs.

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“…In the early stage of RP, the loss of rods triggers a reduction in the expression of rod-derived cone viability factor (RdCVF), encoded by the nucleoredoxin-like 1 (NXNL1) gene, which interrupts the metabolic and redox signaling between rods and cones 15 . The administration of a recombinant AAV encoding the two products of the NXNL1 gene, the trophic factor RdCVF and the thioredoxin enzyme RdCVFL, could theoretically prevent cone vision loss in all genetic forms of RP 16 . We have shown that the NXNL1 gene product, RdCVFL, is expressed in chicken cone-enriched cultures 17 and where it plays a protective role 18 .…”

Section: Introductionmentioning

confidence: 99%

Cone-Enriched Cultures from the Retina of Chicken Embryos to Study Rod to Cone Cellular Interactions

Millet-Puel

Pinault

Cordonnier

et al. 2021

JoVE

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Human daytime vision relies on the function of cone photoreceptors at the center of the retina, the fovea. Patients suffering from the most prevalent form of inherited retinal degeneration, retinitis pigmentosa, lose night vision because of mutation driven loss of rod photoreceptors, a phenomenon followed by a progressive loss of function and death of cones leading to blindness. Geneticists have identified many genes with mutations causing this disease, but the first mutations identified questioned the mechanisms of secondary cone degeneration and how a dominant mutation in the rhodopsin gene encoding for the visual pigment expressed exclusively in rods can trigger cone degeneration. This result of transplantations in a genetic model of the disease led to the concept of cell interactions between rods and cones and of non-cell autonomous degeneration of cones in all genetic forms of retinitis pigmentosa. Cones comprise 5% of all photoreceptors in humans and only 3% in the mouse, so their study is difficult in these species, but cones outnumber rods in bird species. We have adapted 96-well plates to culture retinal precursors from the retina of chicken embryos at stage 29 of their development. In these primary cultures, cones represent 80% of the cells after in vitro differentiation. The cells degenerate over a period of one week in the absence of serum. Here, we describe the methods and its standardization. This cone-enriched culture system was used to identify the epithelium-derived cone viability factor (EdCVF) by high content screening of a rat retinal pigmented epithelium normalized cDNA library. Recombinant EdCVF prevents the degeneration of the cones.

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Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

Cited by 22 publications

References 178 publications

Mutation-Independent Therapies for Retinal Diseases: Focus on Gene-Based Approaches

Mutation-Independent Therapies for Retinal Diseases: Focus on Gene-Based Approaches

The new landscape of retinal gene therapy

Cone-Enriched Cultures from the Retina of Chicken Embryos to Study Rod to Cone Cellular Interactions

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