Casimersen: First Approval

Shirley, Matt

doi:10.1007/s40265-021-01512-2

Cited by 163 publications

(107 citation statements)

References 5 publications

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“…Eteplirsen was eventually approved for Duchenne patients by the FDA, but not by the European Medicines Agency (EMA) [ 136 ]. Golodirsen (or vyondys 53) [ 137 ] and casimersen (or Amondys 45) [ 138 ], two exon-skipping PMO-modified oligonucleotides, also developed by Sarepta Therapeutics, were recently approved by the FDA to treat DMD patients carrying mutations in exon 53 and 45 of the DMD gene, respectively ( Table 3 ).…”

Section: Antisense Mechanisms: Gapmers Sirnas and Splice-modulating Oligonucleotidesmentioning

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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Section: Antisense Mechanisms: Gapmers Sirnas and Splice-modulating Oligonucleotidesmentioning

confidence: 99%

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

Adachi

Hengesbach

et al. 2021

Biomedicines

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“…The use of ASO base-pairing with dystrophin exon 51 (+ASO) promotes its exclusion from the mature mRNA and leads to the translation of a shorter (but functional) protein. For each targeted exon, the ASO approved by the FDA (Food and Drug Administration) are indicated [93][94][95][96][97]; (D) VEGF modRNA used in MI patients [98]. The uridine into pseudouridine substitution is represented by the greek Ψ symbol (red).…”

Section: Small Non-coding Rnasmentioning

confidence: 99%

“…Over the years, the use of ASObased drugs able to convert the out-of-frame mutation to in-frame deletions to produce a shorter, but functional, dystrophin protein has been steadily increasing [126]. To date, the exons targeted by this strategy are represented by exon-51 (Eteplirsen, Drisapersen), exon-53 (Vitolarsen, Golodirsen), and exon-45 (Casimersen) (Figure 2C and Table 1) [93][94][95][96][97]. In particular, Eteplirsen is a 30-nucleotide phosphorodiamidate ASO that induces the skipping of dystrophin exon-51 by impeding the recognition of its splicing sites, thus preventing the formation of a premature stop codon [125].…”

Section: Single-stranded Antisense Oligonucleotides (Aso)mentioning

confidence: 99%

Muscle Regeneration and RNA: New Perspectives for Ancient Molecules

Buonaiuto

Desideri

Taliani

et al. 2021

Cells

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The ability of the ribonucleic acid (RNA) to self-replicate, combined with a unique cocktail of chemical properties, suggested the existence of an RNA world at the origin of life. Nowadays, this hypothesis is supported by innovative high-throughput and biochemical approaches, which definitively revealed the essential contribution of RNA-mediated mechanisms to the regulation of fundamental processes of life. With the recent development of SARS-CoV-2 mRNA-based vaccines, the potential of RNA as a therapeutic tool has received public attention. Due to its intrinsic single-stranded nature and the ease with which it is synthesized in vitro, RNA indeed represents the most suitable tool for the development of drugs encompassing every type of human pathology. The maximum effectiveness and biochemical versatility is achieved in the guise of non-coding RNAs (ncRNAs), which are emerging as multifaceted regulators of tissue specification and homeostasis. Here, we report examples of coding and ncRNAs involved in muscle regeneration and discuss their potential as therapeutic tools. Small ncRNAs, such as miRNA and siRNA, have been successfully applied in the treatment of several diseases. The use of longer molecules, such as lncRNA and circRNA, is less advanced. However, based on the peculiar properties discussed below, they represent an innovative pool of RNA biomarkers and possible targets of clinical value.

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“…Dystrophin-targeting ASOs have been tested in several animal models and patient-derived cell models, and they recently reached the clinical phase. As we mentioned above, four ASOs designed to skip exons 51 (eteplirsen), 53 (golodirsen and viltolarsen) and exon 45 (casimersen) of dystrophin mRNA seem to promote dystrophin restoration in DMD patients, and they have been conditionally approved by the FDA [13][14][15][16]. Limiting factors of this approach include the need for intrathecal injection due to the poor abilities of these drugs to cross the blood-brain barrier (BBB) and the brief half-lives of the drugs, resulting in the need for frequent administrations [3].…”

Section: Hipscs In Thementioning

confidence: 99%

“…As regards DMD treatment, several mutation-specific treatment options have become available for these patients in recent years. In fact, four Food and Drug Administration (FDA)-approved antisense oligonucleotides (ASOs) are currently available for DMD: Exondys 51 (eteplirsen), an exon 51-skipping ASO approved in 2016 [13]; Vyondys 53 (golodirsen) and Viltepso (viltolarsen), two exon 53-skipping ASOs approved in 2019 and in 2020, respectively [14,15]; and Amondys 45 (casimersen), an exon 45-skipping ASO approved in 2021 [16]. Moreover, ataluren, a small-molecule compound administered orally, has been available for the treatment of DMD caused by nonsense mutations since 2014.…”

Section: Introductionmentioning

confidence: 99%

Perspectives on hiPSC-Derived Muscle Cells as Drug Discovery Models for Muscular Dystrophies

Abati

Sclarandi

Comi

et al. 2021

IJMS

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Muscular dystrophies are a heterogeneous group of inherited diseases characterized by the progressive degeneration and weakness of skeletal muscles, leading to disability and, often, premature death. To date, no effective therapies are available to halt or reverse the pathogenic process, and meaningful treatments are urgently needed. From this perspective, it is particularly important to establish reliable in vitro models of human muscle that allow the recapitulation of disease features as well as the screening of genetic and pharmacological therapies. We herein review and discuss advances in the development of in vitro muscle models obtained from human induced pluripotent stem cells, which appear to be capable of reproducing the lack of myofiber proteins as well as other specific pathological hallmarks, such as inflammation, fibrosis, and reduced muscle regenerative potential. In addition, these platforms have been used to assess genetic correction strategies such as gene silencing, gene transfer and genome editing with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), as well as to evaluate novel small molecules aimed at ameliorating muscle degeneration. Furthermore, we discuss the challenges related to in vitro drug testing and provide a critical view of potential therapeutic developments to foster the future clinical translation of preclinical muscular dystrophy studies.

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Casimersen: First Approval

Cited by 163 publications

References 5 publications

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

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

Muscle Regeneration and RNA: New Perspectives for Ancient Molecules

Perspectives on hiPSC-Derived Muscle Cells as Drug Discovery Models for Muscular Dystrophies

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