Molecular Therapies for Inherited Retinal Diseases—Current Standing, Opportunities and Challenges

Vázquez-Domínguez, Irene; Garanto, Alejandro; Collin, Rob W.J.

doi:10.3390/genes10090654

Cited by 69 publications

(74 citation statements)

References 222 publications

(324 reference statements)

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“…We surmise that as more data is being gathered and analyzed, more deep-intronic and non-canonical splice site mutations will come to light [9], not only in IRD genes but also in other Mendelian diseases. Considering that among the most recently reported successful gene therapies for visual disorders, antisense oligonucleotides (AONs) are particularly promising to modulate the effect of splicing mutations [20][21][22][23][24][25], their characterization becomes crucial for patients carrying these variants in order to access these emerging therapies.…”

Section: Discussionmentioning

confidence: 99%

Increasing the Genetic Diagnosis Yield in Inherited Retinal Dystrophies: Assigning Pathogenicity to Novel Non-canonical Splice Site Variants

Toulis

Cortés‐González

Castro-Miró

et al. 2020

Genes

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Aims: We aimed to validate the pathogenicity of genetic variants identified in inherited retinal dystrophy (IRD) patients, which were located in non-canonical splice sites (NCSS). Methods: After next generation sequencing (NGS) analysis (target gene panels or whole exome sequencing (WES)), NCSS variants were prioritized according to in silico predictions. In vivo and in vitro functional tests were used to validate their pathogenicity. Results: Four novel NCSS variants have been identified. They are located in intron 33 and 34 of ABCA4 (c.4774-9G>A and c.4849-8C>G, respectively), intron 2 of POC1B (c.101-3T>G) and intron 3 of RP2 (c.884-14G>A). Functional analysis detected different aberrant splicing events, including intron retention, exon skipping and intronic nucleotide addition, whose molecular effect was either the disruption or the elongation of the open reading frame of the corresponding gene. Conclusions: Our data increase the genetic diagnostic yield of IRD patients and expand the landscape of pathogenic variants, which will have an impact on the genotype–phenotype correlations and allow patients to opt for the emerging gene and cell therapies.

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Section: Discussionmentioning

confidence: 99%

Increasing the Genetic Diagnosis Yield in Inherited Retinal Dystrophies: Assigning Pathogenicity to Novel Non-canonical Splice Site Variants

Toulis

Cortés‐González

Castro-Miró

et al. 2020

Genes

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“…C hannelrhodopsins are light-gated channels first discovered in green (chlorophyte) flagellate algae, in which they serve as photoreceptors mediating phototaxis by depolarization of the cell membrane (1)(2)(3). Currently, channelrhodopsins are widely used for control of neurons and other excitable cells with light ("optogenetics") (4) for research and also in clinical trials to restore vision to the blind (5). Channelrhodopsins from chlorophyte algae conduct cations and are therefore referred to as cation channelrhodopsins (CCRs).…”

mentioning

confidence: 99%

Conductance Mechanisms of Rapidly Desensitizing Cation Channelrhodopsins from Cryptophyte Algae

Sineshchekov

Govorunova

et al. 2020

mBio

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Channelrhodopsins guide algal phototaxis and are widely used as optogenetic probes for control of membrane potential with light. “Bacteriorhodopsin-like” cation channelrhodopsins (BCCRs) from cryptophytes differ in primary structure from other CCRs, lacking usual residues important for their cation conductance. Instead, the sequences of BCCR match more closely those of rhodopsin proton pumps, containing residues responsible for critical proton transfer reactions. We report 19 new BCCRs which, together with the earlier 6 known members of this family, form three branches (subfamilies) of a phylogenetic tree. Here, we show that the conductance mechanisms in two subfamilies differ with respect to involvement of the homolog of the proton donor in rhodopsin pumps. Two BCCRs from the genus Rhodomonas generate photocurrents that rapidly desensitize under continuous illumination. Using a combination of patch clamp electrophysiology, absorption, Raman spectroscopy, and flash photolysis, we found that the desensitization is due to rapid accumulation of a long-lived nonconducting intermediate of the photocycle with unusually blue-shifted absorption with a maximum at 330 nm. These observations reveal diversity within the BCCR family and contribute to deeper understanding of their independently evolved cation channel function. IMPORTANCE Cation channelrhodopsins, light-gated channels from flagellate green algae, are extensively used as optogenetic photoactivators of neurons in research and recently have progressed to clinical trials for vision restoration. However, the molecular mechanisms of their photoactivation remain poorly understood. We recently identified cryptophyte cation channelrhodopsins, structurally different from those of green algae, which have separately evolved to converge on light-gated cation conductance. This study reveals diversity within this new protein family and describes a subclade with unusually rapid desensitization that results in short transient photocurrents in continuous light. Such transient currents have not been observed in the green algae channelrhodopsins and are potentially useful in optogenetic protocols. Kinetic UV-visible (UV-vis) spectroscopy and photoelectrophysiology reveal that the desensitization is caused by rapid accumulation of a nonconductive photointermediate in the photochemical reaction cycle. The absorption maximum of the intermediate is 330 nm, the shortest wavelength reported in any rhodopsin, indicating a novel chromophore structure.

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“…Advanced sequencing methods and the use of cell type-specific transcriptome and proteome and high-throughput screening systems of phenotypic and pleiotropic genetic effects analysis are aimed at identifying target genes associated with inherited diseases and provide prerequisites for better diagnostics, appropriate therapy technologies, and pharmacologic retinal protection [331,335,388,389].…”

Section: Conclusion/insightsmentioning

confidence: 99%

Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes

Markitantova

Симирский

2020

IJMS

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Retinal development is under the coordinated control of overlapping networks of signaling pathways and transcription factors. The paper was conceived as a review of the data and ideas that have been formed to date on homeobox genes mutations that lead to the disruption of eye organogenesis and result in inherited eye/retinal diseases. Many of these diseases are part of the same clinical spectrum and have high genetic heterogeneity with already identified associated genes. We summarize the known key regulators of eye development, with a focus on the homeobox genes associated with monogenic eye diseases showing retinal manifestations. Recent advances in the field of genetics and high-throughput next-generation sequencing technologies, including single-cell transcriptome analysis have allowed for deepening of knowledge of the genetic basis of inherited retinal diseases (IRDs), as well as improve their diagnostics. We highlight some promising avenues of research involving molecular-genetic and cell-technology approaches that can be effective for IRDs therapy. The most promising neuroprotective strategies are aimed at mobilizing the endogenous cellular reserve of the retina.

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Molecular Therapies for Inherited Retinal Diseases—Current Standing, Opportunities and Challenges

Cited by 69 publications

References 222 publications

Increasing the Genetic Diagnosis Yield in Inherited Retinal Dystrophies: Assigning Pathogenicity to Novel Non-canonical Splice Site Variants

Increasing the Genetic Diagnosis Yield in Inherited Retinal Dystrophies: Assigning Pathogenicity to Novel Non-canonical Splice Site Variants

Conductance Mechanisms of Rapidly Desensitizing Cation Channelrhodopsins from Cryptophyte Algae

Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes

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