QR-313, an Antisense Oligonucleotide, Shows Therapeutic Efficacy for Treatment of Dominant and Recessive Dystrophic Epidermolysis Bullosa: A Preclinical Study

Bornert, Olivier; Hogervorst, M.; Nauroy, Pauline; Bischof, Johannes; Swildens, Jim; Athanasiou, Ioannis; Tufa, Sara F.; Keene, Douglas R.; Kiritsi, Dimitra; Hainzl, Stefan; Murauer, Eva M.; Marinkovich, M. Peter; Platenburg, Gerard; Haußer, Ingrid; Wally, Verena; Ritsema, Tita; Koller, Ulrich; Haisma, Elisabeth M.; Nyström, Alexander

doi:10.1016/j.jid.2020.08.018

Cited by 43 publications

(38 citation statements)

References 36 publications

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“…Despite this, an ASO targeting exon 21 encoding a nonsense mutation of the COL4A5 gene successfully improved the clinical phenotypes of a mouse model of Alport syndrome (29) , suggesting that mutations in the in-frame exons of collagen genes are amendable by exon skipping. At the same time, an ASO designed to induce the skipping of exon 73 of the COL7A1 gene, a mutational hotspot, was developed for the treatment of dystrophic epidermolysis bullosa (30) . For dystrophic epidermolysis bullosa, ASOs can be administered topically, opening a new avenue for ASO transfection (30) .…”

Section: Applications Of Exon-skipping Therapiesmentioning

confidence: 99%

Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy

Matsuo

2021

JMA J

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In 1995, we were the first to propose antisense oligonucleotide (ASO)-mediated exon-skipping therapy for the treatment of Duchenne muscular dystrophy (DMD), a noncurable, progressive muscle-wasting disease. DMD is caused by deletion mutations in one or more exons of the DMD gene that shift the translational reading frame and create a premature stop codon, thus prohibiting dystrophin production. The therapy aims to correct out-of-frame mRNAs to produce in-frame transcripts by removing an exon during splicing, with the resumption of dystrophin production. As this treatment is recognized as the most promising, many extensive studies have been performed to develop ASOs that induce the skipping of DMD exons. In 2016, an ASO designed to skip exon 51 was first approved by the Food and Drug Administration, which accelerated studies on the use of ASOs to treat other monogenic diseases. The ease of mRNA editing by ASO-mediated exon skipping has resulted in the further application of exon-skipping therapy to nonmonogenic diseases, such as diabetes mellites. Recently, this precision medicine strategy was drastically transformed for the emergent treatment of only one patient with one ASO, which represents a future aspect of ASO-mediated exon-skipping therapy for extremely rare diseases. Herein, the invention of ASO-mediated exon-skipping therapy for DMD and the current applications of ASO-mediated exon-skipping therapies are reviewed, and future perspectives on this therapeutic strategy are discussed. This overview will encourage studies on ASO-mediated exon-skipping therapy and will especially contribute to the development of treatments for noncurable diseases.

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Section: Applications Of Exon-skipping Therapiesmentioning

confidence: 99%

Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy

Matsuo

2021

JMA J

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“…For example, a clinical trial is currently underway to test the effectiveness of an oligonucleotide that promotes skipping of exon 73 in RDEB patients ( ), and such an oligonucleotide might also be worth testing in our mice. After all, the mutations in our mice are all in exon 73, which is highly conserved between humans and mice, and recent in vitro models suggest that oligonucleotides may also be useful for DDEB ( Bornert et al, 2020 ). Finally, the abundance of genetic tools and experimental methods that are available for mouse-based research – as well as the ability to easily generate sufficient numbers of the animals for well-powered experimental studies – make our DDEB mice well suited to address mechanistic questions related to DDEB pathogenesis.…”

Section: Discussionmentioning

confidence: 96%

Mouse models for dominant dystrophic epidermolysis bullosa carrying common human point mutations recapitulate the human disease

Smith

Nyström

Nowell

et al. 2021

Disease Models &Amp; Mechanisms

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Heterozygous missense mutations in the human COL7A1 gene – coding for collagen VII – lead to the rare, dominantly inherited skin disorder dominant dystrophic epidermolysis bullosa (DDEB), which is characterised by skin fragility, blistering, scarring and nail dystrophy. To better understand the pathophysiology of DDEB and develop more effective treatments, suitable mouse models for DDEB are required but to date none have existed. We identified the two most common COL7A1 mutations in DDEB patients (p.G2034R and p.G2043R) and used CRISPR-Cas9 to introduce the corresponding mutations into mouse Col7a1 (p.G2028R and p.G2037R). Dominant inheritance of either of these two alleles results in a phenotype that closely resembles that seen in DDEB patients. Specifically, mice carrying these alleles show recurrent blistering that is first observed transiently around the mouth and paws in the early neonatal period and then again around the digits from 5-10 weeks of age. Histologically, the mice show micro-blistering and reduced collagen VII immunostaining. Biochemically, collagen VII from these mice displays reduced thermal stability, which we also observed to be the case for DDEB patients carrying the analogous mutations. Unlike previous rodent models of epidermolysis bullosa, which frequently show early lethality and severe disease, these mouse models, which to our knowledge are the first for DDEB, show no reduction in growth and survival, and – together with a relatively mild phenotype – represent a practically and ethically tractable tool for better understanding and treating epidermolysis bullosa. This article has an associated First Person interview with the first author of the paper.

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“…While there are already a few therapeutic oligonucleotides systemically administered, local administration methods have attracted attention. Several examples have been described for local administration: intrathecal [ 41 ], intramuscular [ 42 ], intravitreal injection [ 43 , 44 ], topical [ 45 ], and nebulization/inhalation [ 46 , 47 ].…”

Section: Enabling Technologies For Oligonucleotide Therapeuticsmentioning

confidence: 99%

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

Adachi

Hengesbach

et al. 2021

Biomedicines

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Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation.

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QR-313, an Antisense Oligonucleotide, Shows Therapeutic Efficacy for Treatment of Dominant and Recessive Dystrophic Epidermolysis Bullosa: A Preclinical Study

Cited by 43 publications

References 36 publications

Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy

Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy

Mouse models for dominant dystrophic epidermolysis bullosa carrying common human point mutations recapitulate the human disease

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

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