Viltolarsen: First Approval

Dhillon, Sohita

doi:10.1007/s40265-020-01339-3

Cited by 140 publications

(90 citation statements)

References 8 publications

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“…In general, a severe DMD phenotype can be induced by the following mutation patterns [8][9][10]: out-of-frame large mutations such as deletion of exon 45 and duplication of exon 2; in-frame mutations that disrupt or remove critical domains, including the cysteine-rich domain (exon [64][65][66][67][68][69], all four actin-binding sites (exon 2-8, [42][43][44][45][46], and a great proportion of the central rod domain (exon 9-61); widely distributed nonsense mutations; frame-shift small mutations like c.372delG in exon 6; and splice-site mutations resulting in inclusion of pseudoexons that contain premature termination codons. Those mutations lead to severe DMD pathologies as they produce prematurely truncated, unfunctional dystrophin protein, which will be quickly degraded [12].…”

Section: Correlation Between Mutations and Disease Severitymentioning

confidence: 99%

“…In March 2020, intravenous viltolarsen got its first approval in Japan for treating DMD patients with mutations amenable to exon 53 skipping. Currently, the clinical trials of viltolarsen are undertaken in the United States and Canada [67]. Casimersen, an oligonucleotide that skips exon 45 [54,65], is also in clinical development.…”

Section: Phosphorodiamidate Morpholino Oligomer (Pmo) Modificationmentioning

confidence: 99%

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Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Sun

Shen

Zhang

et al. 2020

Genes

111

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Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.

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Section: Correlation Between Mutations and Disease Severitymentioning

confidence: 99%

Section: Phosphorodiamidate Morpholino Oligomer (Pmo) Modificationmentioning

confidence: 99%

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Sun

Shen

Zhang

et al. 2020

Genes

111

View full text Add to dashboard Cite

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“…These are especially crucial as additional exon skipping therapies are developed. In addition to eteplirsen which skips exon 51, golodirsen (13) and viltolarsen (12), both targeting exon 53, have recently been approved in the US. Thus, for some patients (those with an exon 52 deletion) this is now a clinical reality.…”

Section: Discussionmentioning

confidence: 99%

“…These patients only have access to these two edited choices so far as exon skipping therapy is concerned. Indeed, with the recent approvals of golodirsen and viltolarsen (12,13), this is now a clinical reality for some patients, albeit not for the edits in this study. Table 4.…”

Section: Alternative Exon Skip Repairs For Same Dmd Deletionmentioning

confidence: 90%

“…This leads to a larger, but inframe deletion (the patient's original defect plus the skipped exon). This is not always possible, but where is it, is allows for some dystrophin protein expression, albeit in a modified form The first exon skipping drug, eteplirsen was approved in 2016 (11) , with several others approved recently (12,13) and other in late stage clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Structural Perturbations of Exon Skipping Edits within the Dystrophin D20:24 Region

Niu

Menhart

2020

Preprint

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Exon skipping is a disease modifying therapy that operates at the RNA level. In this strategy, oligonucleotide analog drugs are used to specifically mask specific exons and prevent them from inclusion in the mature mRNA. Of course, this also results in loss of the corresponding region from the cognate protein, which is one possible therapeutic aim. Exon skipping can also be used to restore protein expression in cases where a genetic frameshift mutation has occurred, and this how it is applied to Duchenne muscular dystrophy, DMD. DMD most commonly arises as a result of large exonic deletions that juxtapose flanking exons of incompatible reading frame in the dystrophin gene, creating a frameshift and abolishing protein expression. Loss of dystrophin protein leads to the pathology of the disease, which is severe, causing death generally in the second or third decade of life. Here, the primary aim of exon skipping is the restoration of the reading frame by skipping an exon adjacent to the patient's original defect. However, the therapeutically expressed protein is of course edited, and missing both the region of the underlying genetic defect, as well as the therapeutically skipped exon. While restoring some protein expression is good, how removing some region from the middle of a protein effects its structure and function is unclear. Complicating this in the case of DMD is the fact that the dystrophin gene is very large, containing 79 exons. Many different underlying deletions are known, and exon skipping can be applied in many ways. It has previously been shown that many exon-skip edits result in structural perturbations of varying degrees. What has been unclear is whether and how exon editing can be done to minimize these perturbations. In this study we examine a systematic and comprehensive panel of possible exon edits in a region of the dystrophin protein, and identify for the first time, exon edits that appear to maintain structural stability similar to wildtype protein. We also identify factors that appear to be correlated with the degree of structural perturbation, such as the number of cooperative protein domains, as well as how the underlying exon structure interacts with the protein domain structure.

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PPMOs: A Case Study for Cell‐Penetrating Peptide Application

Bittner

Moulton

2022

Cell‐Penetrating Peptides

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Viltolarsen: First Approval

Cited by 140 publications

References 8 publications

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Structural Perturbations of Exon Skipping Edits within the Dystrophin D20:24 Region

PPMOs: A Case Study for Cell‐Penetrating Peptide Application

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