An update on RNA-targeting therapies for neuromuscular disorders

Jirka, Silvana M.G.; Aartsma‐Rus, Annemieke

doi:10.1097/wco.0000000000000235

Cited by 19 publications

(16 citation statements)

References 44 publications

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“…Since these early studies, targeting splicing with SSOs has been used as a tool to identify cis-acting splicing elements and to modify splicing in ways that are designed to be therapeutic in disease (20). Advances in SSO-based therapeutics and their comparisons to other therapeutic platforms have been extensively reviewed (23,26,39,61–67). Many SSO strategies have now been demonstrated to be effective in modulating splicing in animal models of human disease and some have entered clinical trials (Table 1).…”

Section: Sso Strategies To Therapeutically Manipulate Gene Expressionmentioning

confidence: 99%

“…Today, SSOs targeting numerous DMD exons (8,35,43–45,50,52–55) are being developed as therapies. SSOs that induce skipping of exon 44 (PRO044, BMN 044), exon 45 (SRP-4045, BMN 045), exon 51 (Eteplirsen, Kyndrisa) and exon 53 (SRP-4053, BMN 053) have advanced to clinical trials http://investorrelations.sarepta.com/phoenix.zhtml?c=64231&p=irol-newsArticle&ID=2007537 (67,87,88) (Table 2). Skipping of exon 51 would benefit the most DMD patients, as ∼13% have a frame-shift that could be corrected by the exclusion of this exon from the mRNA (http://www.dmd.nl/) (89) (Figure 4).…”

Section: Splice-modifying Antisense Approaches In Humansmentioning

confidence: 99%

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Splice-switching antisense oligonucleotides as therapeutic drugs

2016

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Splice-switching oligonucleotides (SSOs) are short, synthetic, antisense, modified nucleic acids that base-pair with a pre-mRNA and disrupt the normal splicing repertoire of the transcript by blocking the RNA–RNA base-pairing or protein–RNA binding interactions that occur between components of the splicing machinery and the pre-mRNA. Splicing of pre-mRNA is required for the proper expression of the vast majority of protein-coding genes, and thus, targeting the process offers a means to manipulate protein production from a gene. Splicing modulation is particularly valuable in cases of disease caused by mutations that lead to disruption of normal splicing or when interfering with the normal splicing process of a gene transcript may be therapeutic. SSOs offer an effective and specific way to target and alter splicing in a therapeutic manner. Here, we discuss the different approaches used to target and alter pre-mRNA splicing with SSOs. We detail the modifications to the nucleic acids that make them promising therapeutics and discuss the challenges to creating effective SSO drugs. We highlight the development of SSOs designed to treat Duchenne muscular dystrophy and spinal muscular atrophy, which are currently being tested in clinical trials.

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Section: Sso Strategies To Therapeutically Manipulate Gene Expressionmentioning

confidence: 99%

Section: Splice-modifying Antisense Approaches In Humansmentioning

confidence: 99%

Splice-switching antisense oligonucleotides as therapeutic drugs

2016

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“…These are used to modify pre-mRNA splicing, so that specific exons in the mRNA are removed during splicing 28. The targeted sequence is spliced out as the AON hides the exon splice sites from the splicing machinery 68.…”

Section: Genome Editingmentioning

confidence: 99%

Duchenne muscular dystrophy: genome editing gives new hope for treatment

Crispi

Matsakas

2018

Postgraduate Medical Journal

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Duchenne muscular dystrophy (DMD) is a progressive wasting disease of skeletal and cardiac muscles, representing one of the most common recessive fatal inherited genetic diseases with 1:3500-1:5000 in yearly incidence. It is caused by mutations in the DMD gene that encodes the membrane-associated dystrophin protein. Over the years, many have been the approaches to management of DMD, but despite all efforts, no effective treatment has yet been discovered. Hope for the development of potential therapeutics has followed the recent advances in genome editing and gene therapy. This review gives an overview to DMD and summarises current lines of evidence with regard to treatment and disease management alongside the appropriate considerations.

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“…With the arrival of innovative DM therapies, it is becoming of crucial importance to reach harmonization on the classification of the disease [2][3][4][5][6][7][8][9][10]. In spite of ongoing initiatives involving working-groups of experts, no consensus is yet available.…”

Section: Refining Myotonic Dystrophy Type 1 Clinical Classificationmentioning

confidence: 99%

Progrès dans la classification clinique de la dystrophie myotonique de type 1

et al. 2016

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et le groupe dÊétude français dystrophie myotonique La dystrophie myotonique de type 1 (DM1, maladie de Steinert) est considérée comme l'une des maladies génétiques les plus variables [1]. L'émergence de thérapies innovantes renforce encore la nécessité d'harmoniser, à l'échelon international, la classification clinique de la maladie [2,10]. Malgré les initiatives de groupes de travail d'experts internationaux aucun consensus n'existe à ce jour. Plus récemment, le développement de bases de données fournit de puissants outils pour appréhender la complexité de maladies hétérogènes sur une large population. Nous nous appuyons sur les données de l'Observatoire national des dystrophies myotoniques, DMScope, pour évaluer la robustesse d'une classification de la DM1 en cinq formes cliniques, définies selon l'âge de début de la maladie. L'étude a été réalisée à partir d'une large collection de données standardisées issues de 1 962 patients DM1 français adultes. Les patients ont été classés comme suit : forme congénitale (3,7 %), forme infantile (17,8 %), forme juvénile (25,9 %), forme adulte (39,4 %) et forme tardive (13,1 %). Dans un premier temps, les cinq formes cliniques ont été comparées pour la distribution de la taille de l'expansion CTG, la fré-quence et l'âge d'apparition des principaux symptômes. De plus, nous avons déterminé, grâce à une méthode statistique originale combinant fréquence et temporalité, les profils d'apparition des manifestations cliniques dans chacune des formes. Les résul-tats ont permis de valider le modèle de classification de la DM1 en cinq groupes. Nous montrons qu'audelà du continuum, qui s'étend depuis la forme congénitale jusqu'à la forme tardive, les cinq formes cliniques se distinguent par des particularités cliniques propres. Cette étude confirme la robustesse d'un modèle de classification de la DM1 en cinq formes et met en exergue des caractéristiques cliniques spécifiques à chacune d'elles. Ces résultats devraient permettre d'optimiser le design des essais cliniques et plus particulièrement la constitution de groupes homogènes de patients. Refining myotonic dystrophy type 1 clinical classificationMyotonic dystrophy (DM) is considered to be one of the most variable genetic diseases [1]. With the arrival of innovative DM therapies, it is becoming of crucial importance to reach harmonization on the classification of the disease [2-10]. In spite of ongoing initiatives involving working-groups of experts, no consensus is yet available. Databases are powerful tools to address the complex issue of heterogeneous diseases. Here, we assessed the robustness of a DM1 classification model divided into five clinical forms based on age of onset. The study was performed using a large collection of standardized data obtained in 1,962 French DM1 patients (> 18 years) from the nationwide DM-Scope registry. Patients were classified as follows: congenital (3.7%), infantile (17.8%), juvenile (25.9%), adult (39.4%) and late onset forms (13.1%). The five clinical forms were first compared regarding the ...

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An update on RNA-targeting therapies for neuromuscular disorders

Cited by 19 publications

References 44 publications

Splice-switching antisense oligonucleotides as therapeutic drugs

Splice-switching antisense oligonucleotides as therapeutic drugs

Duchenne muscular dystrophy: genome editing gives new hope for treatment

Progrès dans la classification clinique de la dystrophie myotonique de type 1

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