Cellular Expression and siRNA-Mediated Interference of Rhodopsin<i>cis</i>-Acting Splicing Mutants Associated with Autosomal Dominant Retinitis Pigmentosa

Hernán, Imma; Gamundi, María José; Planas, Ester; Borràs, Emma; Maseras, Miquel; Carballo, Miguel

doi:10.1167/iovs.10-6933

Cited by 19 publications

(14 citation statements)

References 33 publications

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“…Lentiviral delivery of U1snRNA engineered to bind mutated donor splice sites has shown moderate efficacy in rescuing splicing of BBS1 and RPGR in fibroblasts derived from patients with Bardet‐Biedl syndrome and XLRP, respectively. siRNA strategies have been investigated to target variant splice isoforms resulting from adRP‐associated splice site mutations in rhodopsin . Antisense oligonucleotide and related approaches are also being developed to modulate splicing in Duchenne muscular dystrophy, spinal muscular atrophy (SMA), Hutchinson‐Gilford progeria syndrome, and myotonic dystrophy .…”

Section: Small Molecules To Modulate Pre‐mrna Splicingmentioning

confidence: 99%

Alternative splicing and retinal degeneration

Liu

Zack

2013

Clin Genet

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Alternative splicing is highly regulated in tissue-specific and development-specific patterns, and it has been estimated that 15% of disease-causing point mutations affect pre-mRNA splicing. In this review, we consider the cis-acting splice site and trans-acting splicing factor mutations that affect pre-mRNA splicing and contribute to retinal degeneration. Numerous splice site mutations have been identified in retinitis pigmentosa and various cone-rod dystrophies. For example, mutations in alternatively spliced retina-specific exons of the widely expressed RPGR and COL2A1 genes lead primarily to X-linked retinitis pigmentosa and ocular variants of Stickler Syndrome, respectively. Furthermore, mutations in general pre-mRNA splicing factors, such as PRPF31, PRPF8, and PRPF3, predominantly cause autosomal dominant retinitis pigmentosa. These findings suggest an important role for pre-mRNA splicing in retinal homeostasis and the pathogenesis of retinal degenerative diseases. The development of novel therapeutic strategies to modulate aberrant splicing, including small molecule based therapies, has the potential to lead to the development of new treatments for retinal degenerative diseases.

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Section: Small Molecules To Modulate Pre‐mrna Splicingmentioning

confidence: 99%

Alternative splicing and retinal degeneration

Liu

Zack

2013

Clin Genet

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“…This disease affects approximately 1 in 3200, and an estimated 1.5 million people are affected worldwide. The autosomal dominant form of RP (ADRP) is associated with mutations in at least 14 different genes; however, mutations in the rhodopsin gene ( RHO , OMIM 180380, accession ID U49742) are the most prevalent mutation identified to date resulting in 30% to 40% of all ADRP cases [2], [3].…”

Section: Introductionmentioning

confidence: 99%

ER Stress in Retinal Degeneration in S334ter Rho Rats

et al. 2012

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The S334ter rhodopsin (Rho) rat (line 4) bears the rhodopsin gene with an early termination codon at residue 334 that is a model for several such mutations found in human patients with autosomal dominant retinitis pigmentosa (ADRP). The Unfolded Protein Response (UPR) is implicated in the pathophysiology of several retinal disorders including ADRP in P23H Rho rats. The aim of this study was to examine the onset of UPR gene expression in S334ter Rho retinas to determine if UPR is activated in ADRP animal models and to investigate how the activation of UPR molecules leads to the final demise of S334ter Rho photoreceptors. RT-PCR was performed to evaluate the gene expression profiles for the P10, P12, P15, and P21 stages of the development and progression of ADRP in S334ter Rho photoreceptors. We determined that during the P12–P15 period, ER stress-related genes are strongly upregulated in transgenic retinas, resulting in the activation of the UPR that was confirmed using western blot analysis and RT-PCR. The activation of UPR was associated with the increased expression of JNK, Bik, Bim, Bid, Noxa, and Puma genes and cleavage of caspase-12 that together with activated calpains presumably compromise the integrity of the mitochondrial MPTP, leading to the release of pro-apoptotic AIF1 into the cytosol of S334ter Rho photoreceptor cells. Therefore, two major cross-talking pathways, the UPR and mitochondrial MPTP occur in S334ter-4 Rho retina concomitantly and eventually promote the death of the photoreceptor cells.

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“…To prevent the pathological progress of autosomal-dominant RP, rhodopsin mRNA silencing by siRNAs, using two different approaches, has been proposed. The first approach includes the use of allele-specific siRNAs, which block the expression of mutant transcripts while allowing normal expression of wild-type alleles (Hernan et al, 2011). However, the preferential silencing of a common dominant rhodopsin mutation was not sufficient to inhibit retinal degeneration in a transgenic rat model (Tessitore et al, 2006).…”

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confidence: 99%

Small‐interfering RNAs (siRNAs) as a promising tool for ocular therapy

Guzmán-Aránguez

Loma

Pintor

2013

British J Pharmacology

109

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RNA interference (RNAi) can be used to inhibit the expression of specific genes in vitro and in vivo, thereby providing an extremely useful tool for investigating gene function. Progress in the understanding of RNAi-based mechanisms has opened up new perspectives in therapeutics for the treatment of several diseases including ocular disorders. The eye is currently considered a good target for RNAi therapy mainly because it is a confined compartment and, therefore, enables local delivery of small-interfering RNAs (siRNAs) by topical instillation or direct injection. However, delivery strategies that protect the siRNAs from degradation and are suitable for long-term treatment would be help to improve the efficacy of RNAi-based therapies for ocular pathologies. siRNAs targeting critical molecules involved in the pathogenesis of glaucoma, retinitis pigmentosa and neovascular eye diseases (age-related macular degeneration, diabetic retinopathy and corneal neovascularization) have been tested in experimental animal models, and clinical trials have been conducted with some of them. This review provides an update on the progress of RNAi in ocular therapeutics, discussing the advantages and drawbacks of RNAi-based therapeutics compared to previous treatments. AbbreviationsAMD, age-related macular degeneration; Apaf-1, apoptotic protease-activating factor-1; CNV, choroidal neovascularization; CTGF, connective tissue growth factor; DR, diabetic retinopathy; dsRNA, double-stranded RNA; ECM, extracellular matrix; HIF-1α, hypoxia-inducible factor-1α; IOP, intraocular pressure; ONC, optic nerve crush; POAG, open-angle glaucoma; RGC, retinal ganglion cell; RISC, RNA-induced silencing complex; RNAi, RNA interference; RP, retinitis pigmentosa; Smad, signalling mathers against decapentaplegic; SPARC, secreted protein acidic and rich in cysteine; TLR3, toll-like receptor 3; TM, trabecular meshwork; TXNIP, thioredoxin interacting protein IntroductionRNA interference (RNAi) technology has been used to elucidate gene function, to generate model systems and to identify new molecular targets. In addition, RNAi is currently progressing from basic research to potential therapeutic applications. Because any gene that causes or contributes to a disease is susceptible to suppression by RNAi, RNAi therapy represents a promising biomedical strategy for treating a diverse range of diseases including cancer, cardiovascular diseases, neurodegenerative diseases, inflammatory conditions, viral infections and ocular diseases (Guo et al., 2010). In particular, the accessibility of the eye facilitates small-interfering RNA (siRNA) delivery, and naked siRNA has been efficiently applied by topical administration to the anterior segment or by intravitreal injection to the posterior segment (de Fougerolles, 2008). As the localized delivery of siRNA to the eye is less challenging than for other tissues, there has been significant progress made towards its use as a therapeutic procedure for eye diseases. In fact, several siRNA-based therapeutic agents for o...

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Cellular Expression and siRNA-Mediated Interference of Rhodopsincis-Acting Splicing Mutants Associated with Autosomal Dominant Retinitis Pigmentosa

Cited by 19 publications

References 33 publications

Alternative splicing and retinal degeneration

Alternative splicing and retinal degeneration

ER Stress in Retinal Degeneration in S334ter Rho Rats

Small‐interfering RNAs (siRNAs) as a promising tool for ocular therapy

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