- |||||||||| Review, Journal: Impact of Disease-modifying Therapies on Respiratory Function in People with Neuromuscular Disorders. (Pubmed Central) - Aug 3, 2024
The paradigm of care is changing as new disease-modifying therapies are altering disease trajectory, outcomes, expectations, as well as patient and caregiver experiences. This article provides an overview on therapeutic advances for SMA and DMD in the last 10 years, with a focus on the effects of disease-modifying therapies on respiratory function.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Journal: Eteplirsen Treatment for Duchenne Muscular Dystrophy: A Qualitative Patient Experience Study. (Pubmed Central) - Jul 22, 2024
This article provides an overview on therapeutic advances for SMA and DMD in the last 10 years, with a focus on the effects of disease-modifying therapies on respiratory function. This exploratory study indicated that most caregivers perceived improvements or maintenances in aspects of their child's physical functioning, ADLs, and HRQoL since eteplirsen initiation, which they perceived to be a positive outcome.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Journal, Adverse events: Adverse events associated with eteplirsen: A disproportionality analysis using the 2016-2023 FAERS data. (Pubmed Central) - Jul 19, 2024
This has contributed to a deeper understanding of the complex interrelations between adverse reactions and the use of eteplirsen. The findings underscore the critical importance of ongoing monitoring and sustained observation to promptly detect and effectively manage AEs, thereby enhancing the overall safety and well-being of patients treated with eteplirsen for DMD.
- |||||||||| Translarna (ataluren) / PTC Therap, Exondys 51 (eteplirsen) / Sarepta Therap, Emflaza (deflazacort) / Marathon, PTC Therap
Retrospective data, Review, Journal, IO biomarker: Predictors of Loss of Ambulation in Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis. (Pubmed Central) - May 3, 2024
Glucocorticoid therapy was associated with delayed loss of ambulation (overall meta-analysis HR deflazacort/prednisone/prednisolone: 0.44 [95% CI: 0.40-0.48]) (n?=?25 studies)...Treatment with ataluren (n?=?2 studies) and eteplirsen (n?=?3 studies) were associated with prolonged ambulation...In total, 33% of studies exhibited some risk of bias. Our synthesis of predictors of loss of ambulation in DMD contributes to the understanding the natural history of disease and informs the design of new trials of novel therapies targeting this heavily burdened patient population.
- |||||||||| Journal: Characteristics of Patients Receiving Novel Muscular Dystrophy Drugs in Trials vs Routine Care. (Pubmed Central) - Jan 24, 2024
These findings raise questions about the translation of DMD drug trial findings to routine care settings, with patients in routine care discontinuing the treatment within 1 year and payers incurring substantial expenses for these medications. More data are needed on whether these high costs are accompanied by corresponding clinical benefits.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Cas12 DNA editing restores dystrophin expression and muscle function in mouse model of Duchenne muscular dystrophy and demonstrates high editing efficiency in NHPs () - Oct 15, 2023 - Abstract #ESGCT2023ESGCT_930;
Here, we generated a novel humanized DMD mouse model harboring human DMD exon51, which exhibited highly similar phenotypes in patients with DMD...In addition, no in vivo toxicities were observed, including nerve, liver, and kidney injury, in the humanized DMD mice and WT NHPs. Unlike antisense?oligonucleotide?based exon skipping therapy administering throughout a patient's lifetime or AAV gene replacement therapy expressing micro?dystrophins for partial dystrophin functionality, our innovative CRISPR?based hfCas12Max?mediated single?cut approach modifying genomic DNA offers a promising, long?lasting, and "one?and?done" new treatment modality that targets the underlying cause of DMD.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Amondys 45 (casimersen) / Sarepta Therap
Trial completion: A 48-Week, Open Label, Study to Evaluate the Efficacy and Safety of AMONDYS 45, EXONDYS 51, VYONDYS 53 in Subjects With DuchenneMuscular Dystrophy Carrying Eligible DMD Duplications. (clinicaltrials.gov) - Oct 12, 2023
P2, N=3, Completed,
Unlike antisense?oligonucleotide?based exon skipping therapy administering throughout a patient's lifetime or AAV gene replacement therapy expressing micro?dystrophins for partial dystrophin functionality, our innovative CRISPR?based hfCas12Max?mediated single?cut approach modifying genomic DNA offers a promising, long?lasting, and "one?and?done" new treatment modality that targets the underlying cause of DMD. Active, not recruiting --> Completed
- |||||||||| Review, Journal: Advances in Dystrophinopathy Diagnosis and Therapy. (Pubmed Central) - Oct 4, 2023
Other antisense oligonucleotide drugs in the pipeline include casimersen for exon 45, suvodirsen for exon 51, and golodirsen for exon 53 skipping. Advances in the diagnosis and therapy of dystrophinopathies offer new perspectives for their early discovery and care.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Review, Journal: The Regulatory Repercussions of Approving Muscular Dystrophy Medications on the Basis of Limited Evidence. (Pubmed Central) - Aug 21, 2023
Despite recent legislative and regulatory changes to the FDA's accelerated approval pathway, the history of eteplirsen and similar drugs points to the need for additional reforms to better balance evidence generation with patient safety and access to promising medications. Lawmakers and regulators should take further action to limit excessive spending on unproven therapies and ensure that drug sponsors conduct robust and timely confirmatory trials after receiving accelerated approval.
- |||||||||| Review, Journal: The potential role and mechanism of circRNA/miRNA axis in cholesterol synthesis. (Pubmed Central) - Jun 20, 2023
Suppressing HMGCR, SQLE, and miR-122 with circRNA_ABCA1, circ-PRKCH, circEZH2, circRNA-SCAP, and circFOXO3 are the promising therapeutic target for drug development, specifically the circFOXO3. This review focuses on the role and mechanism of the circRNA/miRNA axis in cholesterol synthesis in the hope of providing knowledge to identify new targets.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap, Kyndrisa (drisapersen) / BioMarin
Journal: Next Generation Exon 51 Skipping Antisense Oligonucleotides for Duchenne Muscular Dystrophy. (Pubmed Central) - Jun 8, 2023
These dystrophin levels allowed for normalization of creatine kinase (CK) and lactate dehydrogenase (LDH) levels, and improved motor function in hDMDdel52/mdx mice. As no major safety observation was obtained, the improved therapeutic index of these next generation AONs is encouraging for further (pre)clinical development.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Exondys 51 (eteplirsen) / Sarepta Therap, Amondys 45 (casimersen) / Sarepta Therap
Interim Analysis of EVOLVE: A Long-term Observational Study Evaluating Eteplirsen, Golodirsen, or Casimersen in Routine Clinical Practice (Foyer 3B, 3rd Floor) - May 29, 2023 - Abstract #EPNS2023EPNS_815;
As no major safety observation was obtained, the improved therapeutic index of these next generation AONs is encouraging for further (pre)clinical development. These real-world data from the interim analysis of EVOLVE support the safety profiles and will continue to describe long-term clinical outcomes of eteplirsen, golodirsen, and casimersen.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Single-Cut Gene Editing Therapy for Duchenne Muscular Dystrophy via a Single AAV Vector (Board No. 951) - Apr 21, 2023 - Abstract #ASGCT2023ASGCT_1673;
This unique DMD mouse model with the human genomic sequence allows in vivo assessment of clinically relevant gene editing strategies as well as other therapeutic approaches. Research on improving present antisense-based therapeutic strategies represents a significant step toward therapeutic translation of gene editing correction of patients with DMD.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Small Nuclear RNA-Mediated Exon 51 Skipping AAV9 Gene Therapy for the Treatment of Duchenne Muscular Dystrophy (Board No. 1198) - Apr 21, 2023 - Abstract #ASGCT2023ASGCT_1402;
In summary, our novel designs allow for high-titer viral packaging of full-length AAV genomes carrying multiple highly expressing snRNA cassettes which we show to effectively skip DMD exon 51 and which can be rapidly deployed to therapeutically skip other DMD exons by switching antisense targeting sequences...3. Megan Waldrop, ASGCT 2022.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Precise Correction of Duchenne Muscular Dystrophy with Exon 51 Deletion by Adenine Base Editing-Induced Exon Skipping in a Humanized Mouse Model (Board No. 667) - Apr 21, 2023 - Abstract #ASGCT2023ASGCT_1357;
Here, we target the correction of the DMD exon51 deletion mutation by exon-skipping therapy of the exon50 which may therapeutically benefit DMD patients... This unique DMD mouse model with the human genomic sequence allows in vivo assessment of clinically relevant CRISPR ABE gene-editing strategies as well as other therapeutic approaches and represents a significant step toward therapeutic translation of adenine base editing for correction of patients with DMD or other genetic neuromuscular diseases.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Exondys 51 (eteplirsen) / Sarepta Therap, Viltepso (viltolarsen) / Nippon Shinyaku
Preclinical, Journal: In Vivo Evaluation of Exon 51 Skipping in hDMD/Dmd-null Mice. (Pubmed Central) - Apr 4, 2023
A solution to this issue is to use double mutant hDMD/Dmd-null mice, which only carry the human DMD sequence and are null for the mouse Dmd sequence. Here, we describe intramuscular and intravenous injections of an ASO to skip exon 51 in hDMD/Dmd-null mice, and the evaluation of its efficacy in vivo.
- |||||||||| Review, Journal: Recent Trends in Antisense Therapies for Duchenne Muscular Dystrophy. (Pubmed Central) - Mar 30, 2023
These upcoming therapies often utilize novel drug chemistries to address limitations of existing therapies, and their development could herald the next generation of antisense therapy. This review article aims to summarize the current state of development for antisense-based therapies for the treatment of Duchenne muscular dystrophy, exploring candidates designed for both exon skipping and gene knockdown.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Journal: High-capacity adenovector delivery of forced CRISPR-Cas9 heterodimers fosters precise chromosomal deletions in human cells. (Pubmed Central) - Mar 21, 2023
Finally, all-in-one AdVP delivery of forced CRISPR-Cas9 heterodimers triggers robust DMD exon 51 splice site excision resulting in reading frame restoration and selection-free detection of dystrophin in muscle cells derived from Duchenne muscular dystrophy patients. In conclusion, AdVPs promote precise multiplexing genome editing through the integrated delivery of forced CRISPR-Cas9 heterodimer components, which, in comparison with split conventional CRISPR-Cas9 multiplexes, engage target sequences in a more coordinated fashion.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Amondys 45 (casimersen) / Sarepta Therap
Trial completion date: A 48-Week, Open Label, Study to Evaluate the Efficacy and Safety of AMONDYS 45, EXONDYS 51, VYONDYS 53 in Subjects With DuchenneMuscular Dystrophy Carrying Eligible DMD Duplications. (clinicaltrials.gov) - Nov 29, 2022
P2, N=3, Active, not recruiting,
In conclusion, AdVPs promote precise multiplexing genome editing through the integrated delivery of forced CRISPR-Cas9 heterodimer components, which, in comparison with split conventional CRISPR-Cas9 multiplexes, engage target sequences in a more coordinated fashion. Trial completion date: Sep 2022 --> Sep 2023
- |||||||||| Journal: Restoring Dystrophin Expression by Skipping Exons 6 and 8 in Neonatal Dystrophic Dogs. (Pubmed Central) - Nov 20, 2022
In this chapter, we describe the systemic delivery of a cocktail of four PMOs that can successfully induce multiple exon skipping (exons 6-9) in neonatal dystrophic dogs. We also describe the procedures to evaluate the efficacy and toxicity, including clinical grading of dystrophic dogs, ELISA-based quantification of PMOs, histology, RT-PCR, and western blotting.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Exondys 51 (eteplirsen) / Sarepta Therap, Amondys 45 (casimersen) / Sarepta Therap
Interim analysis of EVOLVE: a long-term observational study evaluating Eteplirsen, Golodirsen, or Casimersen in routine clinical practice (Virtual platform and E-Posters only) - Nov 5, 2022 - Abstract #WMS2022WMS_519;
Median age at LOA for eteplirsen-treated patients is 15.3 years, consistent with prior clinical trial post-hoc results; small sample size to date precludes analysis of age at LOA for golodirsen or casimersen. These real-world data from the interim analysis of EVOLVE support the safety profiles and will continue to describe long-term clinical outcomes of eteplirsen, golodirsen, and casimersen.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Journal: Gene editing of Duchenne muscular dystrophy using biomineralization-based spCas9 variant nanoparticles. (Pubmed Central) - Oct 16, 2022
We evaluated multiple target regions with different PAMs for the DMD exon 51 splice acceptor site through Bm-SpRY NPs method and found that the target region with TAG PAM has the highest editing efficiency and significant preferential mutation...Here, the present study provides a biomineralized PAM Less Cas9 (SpRY) variant nanoparticles (Bm-SpRY NPs) for DMD gene editing in vitro and in vivo. This study may extend the application of CRISPR system for DMD gene therapy.
- |||||||||| Review, Journal: Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets. (Pubmed Central) - Sep 3, 2022
In this last case, the use of ASOs permits modifying the expression of specific proteins by modulating splicing of specific pre-RNAs (e.g., Nusinersen acts on the splicing of exon 7 in SMN2 mRNA normally not expressed; it is used for spinal muscular atrophy) or by downregulation of transcript levels (e.g., Inotersen acts on the transthryretin mRNA to reduce its expression; it is prescribed for the treatment of hereditary transthyretin amyloidosis) in order to restore the biochemical/physiological condition and ameliorate quality of life...In this review, we summarize the main transcriptional therapeutic drugs approved to date for the treatment of genetic diseases by principal regulatory government agencies and recent clinical trials aimed at the treatment of cancer. Their mechanism of action, chemical structure, administration, and biomedical performance are predominantly discussed.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Journal: Delays in pulmonary decline in eteplirsen-treated patients with Duchenne muscular dystrophy. (Pubmed Central) - Aug 24, 2022
Their mechanism of action, chemical structure, administration, and biomedical performance are predominantly discussed. The attenuation of FVC%p decline suggests that eteplirsen-treated patients had statistically significant and clinically meaningful attenuations in pulmonary decline compared with SoC patients.
- |||||||||| Building a FORCETM platform-based DMD franchise for the treatment of individuals with mutations amenable to exon skipping (Poster area - Ballroom B1-B2) - Aug 20, 2022 - Abstract #WMS2022WMS_306;
FORCE-M23D is a mouse-specific Fab-PMO conjugate designed to target TfR1 and skip exon 23 of the murine Dmd transcript to restore dystrophin expression in the mdx mouse model of DMD...Additionally, Dyne's clinical candidate, DYNE-251, a Fab-conjugated PMO designed to skip DMD exon 51, was evaluated in non-human primates (NHPs)...Lastly, we have begun development of FORCE conjugates for the treatment of exon 53 and exon 45 skipping amenable patients...This conjugate resulted in superior skipping of exon 53 compared to unconjugated PMO. Collectively, these data support utilizing the FORCE platform for the development of therapies for individuals with DMD mutations amenable to exon skipping.
- |||||||||| FDA event, Journal: Absorption, distribution, metabolism, and excretion of FDA-approved antisense oligonucleotide drugs. (Pubmed Central) - Jun 25, 2022
Significance Statement Through a systematic analysis of the existing information of ADME parameters for ten FDA-approved ASO drugs, this review provides an overall view of the unique ADME characteristics of ASO drugs, which are distinct from small chemical drug ADME. This knowledge is useful for discovery and development of new ASO drugs as well as clinical use of current FDA-approved ASO drugs.
- |||||||||| FDA event, Journal, Adverse drug reaction: Adverse Drug Reactions and Toxicity of the FDA-approved Antisense Oligonucleotide Drugs. (Pubmed Central) - Jun 25, 2022
Significance Statement The current review provides a comprehensive analysis of unique and common ADRs and the toxicity of FDA-approved ASO drugs. The information can help better manage the risk of severe hepatotoxicity, kidney toxicity, and hypersensitivity reactions in the usage of currently approved ASO drugs and the discovery and development of new and safer ASO drugs.
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