Casimersen for the treatment of Duchenne muscular dystrophy

Zakeri, Shahab Edalatian; Pradeep, Sai Pallavi; Kasina, Vishal; Laddha, Ankit P.; Manautou, José E.; Bahal, Raman

doi:10.1016/j.tips.2022.04.009

Cited by 15 publications

(11 citation statements)

References 6 publications

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“…58 Finally, casimersen was approved in 2021 for patients amenable to 45 skipping. 59 Data on the impact of exon skipping on respiratory function is only available for eteplirsen and golodirsen. 57,60,61 Respiratory function was assessed in twelve patients and compared to an untreated group.…”

Section: Novel Therapiesmentioning

confidence: 99%

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ATS Core Curriculum 2022. Pediatric Pulmonary Medicine: Updates in pediatric neuromuscular disease

Leon‐Astudillo

Okorie

McCown

et al. 2023

Pediatric Pulmonology

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The American Thoracic Society Core Curriculum updates clinicians annually in pediatric pulmonary disease. This is a concise review of the Pediatric Pulmonary Medicine Core Curriculum presented at the 2022 American Thoracic Society International Conference. Neuromuscular diseases (NMD) comprise a variety of conditions that commonly affect the respiratory system and cause significant morbidity including dysphagia, chronic respiratory failure, and sleep disordered breathing. Respiratory failure is the most common cause of mortality in this population. Substantial progress has been made in diagnosis, monitoring and treatment for NMD over the last decade. Pulmonary function testing (PFT) is utilized to objectively measure respiratory pump function and PFT milestones are utilized in NMD‐specific pulmonary care guidelines. New disease modifying therapies are approved for the treatment of patients with Duchenne muscular dystrophy and spinal muscular atrophy (SMA), including the first ever approved systemic gene therapy, in the case of SMA. Despite extraordinary progress in the medical management of NMD, little is known regarding the respiratory implications and long‐term outcomes for patients in the era of advanced therapeutics and precision medicine. The combination of technological and biomedical advancements has increased the complexity of the medical decision‐making process for patients and families, thus emphasizing the importance of balancing respect for autonomy with the other foundational principles of medical ethics. This review features an overview of PFT, noninvasive ventilation strategies, novel and developing therapies, as well as the ethical considerations specific to the management of patients with pediatric NMD.

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Section: Novel Therapiesmentioning

confidence: 99%

“…Viltolarsen was approved in August 2020 also for patients amenable to exon 53 skipping based on an increase in dystrophin to 6% of normal 58 . Finally, casimersen was approved in 2021 for patients amenable to 45 skipping 59 …”

Section: Introductionmentioning

confidence: 99%

ATS Core Curriculum 2022. Pediatric Pulmonary Medicine: Updates in pediatric neuromuscular disease

Leon‐Astudillo

Okorie

McCown

et al. 2023

Pediatric Pulmonology

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“…Smallmolecule medication ataluren (Translarna) is administered to skip the terminators produced by mutations and express functional dystrophin isoforms, thus alleviating disease progression. Oligomeric antisense nucleotides, such as golodirsen (Vyondys 53), 12,13 casimersen (Amondys 45), 14,15 and eteplirsen (Exondys 51), 16 specifically recognize the pre-mRNA and bind with it. 17 As a result, they promote the expression of functional dystrophin and play a therapeutic role.…”

Section: Introductionmentioning

confidence: 99%

Duchenne muscular dystrophy treatment with lentiviral vector containing mini‐dystrophin gene in vivo

Wang,

Zhu,

Liu

et al. 2024

MedComm

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Duchenne muscular dystrophy (DMD) is an incurable X‐linked recessive genetic disease caused by mutations in the dystrophin gene. Many researchers aim to restore truncated dystrophin via viral vectors. However, the low packaging capacity and immunogenicity of vectors have hampered their clinical application. Herein, we constructed four lentiviral vectors with truncated and sequence‐optimized dystrophin genes driven by muscle‐specific promoters. The four lentiviral vectors stably expressed mini‐dystrophin in C2C12 muscle cells in vitro. To estimate the treatment effect in vivo, we transferred the lentiviral vectors into neonatal C57BL/10ScSn‐Dmdmdx mice through local injection. The levels of modified dystrophin expression increased, and their distribution was also restored in treated mice. At the same time, they exhibited the restoration of pull force and a decrease in the number of mononuclear cells. The remissions lasted 3–6 months in vivo. Moreover, no integration sites of vectors were distributed into the oncogenes. In summary, this study preliminarily demonstrated the feasibility and safety of lentiviral vectors with mini‐dystrophin for DMD gene therapy and provided a new strategy to restore truncated dystrophin.

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“…ASOs are also useful for generating a partially functional truncated protein by causing exon skipping to restore in-frame reading of the dystrophin gene to achieve a treatment for Duchenne muscular dystrophy (DMD). Eteplirsen, which was approved by the FDA in September 2016, is designed to promote the in-frame skipping of dystrophin’s Exon 51 [ 18 ], whereas golodirsen (which was approved in December 2019) is designed to cause the skipping of Exon 53 [ 19 , 20 ], and casimersen causes the skipping of Exon 45 [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

A Potential Therapy Using Antisense Oligonucleotides to Treat Autosomal Recessive Polycystic Kidney Disease

Wang

Che

et al. 2023

JCM

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(1) Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by progressively enlarged kidneys with fusiform dilatation of the collecting ducts. Loss-of-function mutations in the PKHD1 gene, which encodes fibrocystin/polyductin, cause ARPKD; however, an efficient treatment method and drug for ARPKD have yet to be found. Antisense oligonucleotides (ASOs) are short special oligonucleotides which function to regulate gene expression and alter mRNA splicing. Several ASOs have been approved by the FDA for the treatment of genetic disorders, and many are progressing at present. We designed ASOs to verify whether ASOs mediate the correction of splicing further to treat ARPKD arising from splicing defects and explored them as a potential treatment option. (2) Methods: We screened 38 children with polycystic kidney disease for gene detection using whole-exome sequencing (WES) and targeted next-generation sequencing. Their clinical information was investigated and followed up. The PKHD1 variants were summarized and analyzed, and association analysis was carried out to analyze the relationship between genotype and phenotype. Various bioinformatics tools were used to predict pathogenicity. Hybrid minigene analysis was performed as part of the functional splicing analysis. Moreover, the de novo protein synthesis inhibitor cycloheximide was selected to verify the degraded pathway of abnormal pre-mRNAs. ASOs were designed to rescue aberrant splicing, and this was verified. (3) Results: Of the 11 patients with PKHD1 variants, all of them exhibited variable levels of complications of the liver and kidneys. We found that patients with truncating variants and variants in certain regions had a more severe phenotype. Two splicing variants of the PKHD1 genotypes were studied via the hybrid minigene assay: variants c.2141-3T>C and c.11174+5G>A. These cause aberrant splicing, and their strong pathogenicity was confirmed. We demonstrated that the abnormal pre-mRNAs produced from the variants escaped from the NMD pathway with the use of the de novo protein synthesis inhibitor cycloheximide. Moreover, we found that the splicing defects were rescued by using ASOs, which efficiently induced the exclusion of pseudoexons. (4) Conclusion: Patients with truncating variants and variants in certain regions had a more severe phenotype. ASOs are a potential drug for treating ARPKD patients harboring splicing mutations of the PKHD1 gene by correcting the splicing defects and increasing the expression of the normal PKHD1 gene.

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Casimersen for the treatment of Duchenne muscular dystrophy

Cited by 15 publications

References 6 publications

ATS Core Curriculum 2022. Pediatric Pulmonary Medicine: Updates in pediatric neuromuscular disease

ATS Core Curriculum 2022. Pediatric Pulmonary Medicine: Updates in pediatric neuromuscular disease

Duchenne muscular dystrophy treatment with lentiviral vector containing mini‐dystrophin gene in vivo

A Potential Therapy Using Antisense Oligonucleotides to Treat Autosomal Recessive Polycystic Kidney Disease

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