Exondys 51 (eteplirsen) / Sarepta Therap - LARVOL DELTA

Anti-PF4 antibodies are a potential mediator of antisense oligonucleotide (ASO)-induced thrombocytopenia. (ASH 2025) - "Twelve ASOs, Inotersen, Eplontersen,Olezarsen, Fomivirsen, Mipomersen, Tofersen, Nusinersen, Eteplirsen, Golodirsen, Viltolarsen,Casimersen (all FDA approved) and Volanesorsen (EMA approved) were evaluated in this study. With two ASOs, Fomivirsen and Eteplirsen, direct activation of platelets was noted. Studieswith additional ASOs revealed a novel immune mechanism involving ASO-PF4 complex formation andanti-PF4 antibody recognition that can plausibly mediate ASO-induced thrombocytopenia. These findingshighlight the key role PS linkages may play in ASO immunogenicity and provide a mechanistic frameworkfor risk mitigation in ASO drug design, supporting the safer development and broader application of ASOtherapeutics."

Hematological Disorders • Thrombocytopenia

Nephrotoxicity of Antisense Oligonucleotide Therapies in Duchenne Muscular Dystrophy: A Warning or a Challenge? (ISPOR-EU 2025) - "In the US Golodirsen, Viltolarsen, Eteplirsen and Casimersen are approved (conditionally) to treat DMD...Specific cases include: i) Drisapersen, terminated due to a poor benefit-risk profile, with notable renal toxicity, ii) Vesleteplirsen, associated with severe hypomagnesemia and hypokalemia... Patients with DMD treated with ONA require vigilant renal monitoring. Recommendations include regular assessment of renal biomarkers (e.g., proteinuria, creatinine), adjustment of corticosteroids, and preference for inactivated or conjugated vaccines."

Duchenne Muscular Dystrophy • Genetic Disorders • Inflammation • Muscular Dystrophy • Nephrology • Rare Diseases • Renal Disease

Superior editing efficiency and small size of CRISPR/hfCas12Max for gene and cell therapy applications (ESGCT 2024) - "After systemic delivery of a single all-in-one AAV vector that contained hfCas12Max along with a gRNA targeting the splice donor (SD) site of human DMD exon 51 to the Duchenne Muscular Dystrophy (DMD) mouse model, we observed efficient restoration of dystrophin expression...Our findings suggest that hfCas12Max, with its robust editing activity and high specificity, is a promising tool for safer and more effective gene and cell therapy treatments. Synthetic guide RNAs and purified nuclease for hfCas12Max are now readily available for CRISPR medicine developers through Synthego Corporation, USA, as part of a strategic partnership with HuidaGene to enhance the accessibility and efficiency of the CRISPR tools."

Amyotrophic Lateral Sclerosis • CNS Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Muscular Dystrophy

CRISPR/hfCas12Max-based single-cut gene-editing therapy restores dystrophin expression and muscle performance in mouse models of Duchenne muscular dystrophy to support the initiation of MUSCLE clinical trial (ESGCT 2024) - "The antisense oligonucleotide medicines, known as Eteplirsen or Casimersen, have been approved to treat DMD patients with exon 45–55 hotspot region mutations. Our novel discovery of hfCas12Max nuclease and rigorously designed and executed in vitro and in vivo tests support the clinical development of an ‘all-in-one’ AAV with the CRISPR/hfCas12Max gene-editing therapy for DMD patients. The U.S. FDA has granted orphan drug and rare pediatric disease designations to HG302 for treating DMD."

Preclinical • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • Pediatrics

Development and future prospects of exon-skipping therapy for Duchenne muscular dystrophy. (PubMed, Brain Dev) - "In 2016, eteplirsen, which induces exon 51 skipping, received accelerated approval in the United States...The establishment of an early diagnostic system may also need to be considered. The present review outlines the development and future challenges of exon-skipping therapy for DMD and the expansion of splice-switching therapy (a therapy that uses AS-oligo to control splicing), including exon-skipping therapy, to other diseases."

Journal • Review • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

The Utilization, Reimbursement, and Cost of Targeted Therapies for Duchenne Muscular Dystrophy (DMD) in US Medicaid Programs: A Descriptive Trend Analysis from 2017 to 2022. (PubMed, Pharmaceut Med) - "The considerable rise in the utilization and spending of novel DMD drugs has imposed a significant burden on the Medicaid budget, underlining the need for policy measures to manage rising costs and maintain equal access to treatment."

Journal • Reimbursement • US reimbursement • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Association between exon-skipping therapy with eteplirsen and cardiac outcomes in Duchenne muscular dystrophy. (PubMed, J Neuromuscul Dis) - "Annual rate of LVEF decline for eteplirsen-treated and controls was -0.66% (95% CI = -0.96 to -0.36, P < 0.01) and -1.38% (95% CI = -1.60 to -1.16; P < 0.01), respectively. Results were consistent with a sensitivity analysis matching each eteplirsen-treated patient once with a unique control patient and with several tests for potential bias.ConclusionsIn this retrospective study, eteplirsen-treated patients were observed to have a significantly lower risk of reaching LVEF thresholds indicative of cardiac function decline and attenuation of LVEF decline compared with matched controls."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Duchenne Muscular Dystrophy • Genetic Disorders • Heart Failure • Muscular Dystrophy

An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases. (PubMed, Methods Mol Biol) - "The US Food and Drug Administration (FDA) has granted accelerated approval for four AONs to skip a single DMD exon for treating patients with DMD: eteplirsen for exon 51 skipping, golodirsen and viltolarsen for exon 53 skipping, and casimersen for exon 45 skipping. Splice-modulating AONs have also been extensively tested in other inherited diseases, such as Usher syndrome, dystrophic epidermolysis bullosa (DEB), fibrodysplasia ossificans progressiva (FOP), and allergic diseases. This chapter will introduce the developmental status of exon skipping and splice-modulating therapies for genetic diseases."

Journal • Allergy • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Inherited Retinal Dystrophy • Muscular Dystrophy • Myositis • Myotonic Dystrophy • Ophthalmology

Tips to Design Effective Splice-Switching Antisense Oligonucleotides for Exon Skipping and Exon Inclusion. (PubMed, Methods Mol Biol) - "The approval of Exondys 51 (eteplirsen) and Spinraza (nusinersen) for the treatment of patients with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) was the most noteworthy accomplishment in 2016...The mechanism of mRNA splicing is highly complex, and the efficacy of AONs are often unpredictable. We will discuss the design of effective AONs for exon skipping and exon inclusion in this chapter."

Journal • Becker Muscular Dystrophy • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Myositis • Rare Diseases

Direct Reprogramming of Human DMD Fibroblasts into Myotubes for In Vitro Evaluation of Antisense-Mediated Exon Skipping and Exons 45-55 Skipping Accompanied by Rescue of Dystrophin Expression. (PubMed, Methods Mol Biol) - "To overcome these challenges, researchers can generate myofibers from patient fibroblast cells by transducing the cells with a viral vector containing MyoD, a myogenic regulatory factor. Here, we describe a methodology for assessing dystrophin exons 45-55 multiple skipping efficiency using antisense oligonucleotides in human muscle cells derived from DMD patient fibroblast cells."

Journal • Preclinical • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Creation of DMD Muscle Cell Model Using CRISPR-Cas9 Genome Editing to Test the Efficacy of Antisense-Mediated Exon Skipping. (PubMed, Methods Mol Biol) - "The approval of Exondys 51 (eteplirsen) targeting exon 51 was the most noteworthy accomplishment in 2016...Furthermore, many DMD mutations are very rare and it is hard to find a patient with a specific mutation for muscle biopsy in many cases. Here, we describe a novel approach to create an immortalized muscle cell line with a DMD deletion mutation using the human rhabdomyosarcoma (RD) cell line and the CRISPR/Cas9 system that can be used to test the efficacy of exon skipping."

Journal • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor

In Vivo Evaluation of Multiple Exon Skipping with Peptide-PMOs in Cardiac and Skeletal Muscles in Dystrophic Dogs. (PubMed, Methods Mol Biol) - "The FDA conditionally approved the first exon skipping AON, called eteplirsen (brand name ExonDys51), targeting exon 51 of the DMD gene, in late 2016...Although the success of multiple exon skipping in a DMD dog model has made a significant impact on the development of therapeutics for DMD, unmodified AONs such as phosphorodiamidate morpholino oligomers (PMOs) have little efficacy in cardiac muscles. Here, we describe the systemic delivery of a cocktail of peptide-conjugated PMOs (PPMOs) to skip multiple exons in both skeletal and cardiac muscles in dystrophic dogs and the evaluation of the efficacies and toxicity in vivo."

Journal • Preclinical • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Morpholino-Mediated Exon Skipping Targeting Human ACVR1/ALK2 for Fibrodysplasia Ossificans Progressiva. (PubMed, Methods Mol Biol) - "Here, we describe a method to reduce ACVR1 expression in FOP patient cells by exon skipping in ACVR1 mRNAs using phosphorodiamidate morpholino oligomers (PMOs). This strategy can be applied to the screen to select antisense oligomers to knockdown not only ACVR1 but also genes which cause other autosomal-dominant genetic diseases."

Journal • Genetic Disorders • Musculoskeletal Diseases • ACVR1

Systemic Injection of Peptide-PMOs into Humanized DMD Mice and Detection by RT-PCR and ELISA. (PubMed, Methods Mol Biol) - "Researchers have previously relied on high-performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC/MS) methods for detecting PPMO uptake, but an enzyme-linked immunosorbent assay (ELISA) has been shown to have greater sensitivity. Here, we present methodologies to determine the uptake efficiency of a PPMO into the heart and efficacy of exon 51 skipping by a PPMO injected retro-orbitally into a humanized DMD mouse model via ELISA and RT-PCR, respectively."

Journal • Preclinical • Becker Muscular Dystrophy • Cardiovascular • Congestive Heart Failure • Duchenne Muscular Dystrophy • Genetic Disorders • Heart Failure • Muscular Dystrophy • Respiratory Diseases

In Vivo Evaluation of Single- and Multi-Exon-Skipping in mdx52 Mice. (PubMed, Methods Mol Biol) - "Multi-exon-skipping utilizing ASOs can theoretically treat 80-90% of patients with DMD. Here, we describe the systemic delivery of a cocktail of ASOs to skip exon 51 and exons 45 to 55 in the mdx52 mouse, an exon 52 deletion model of DMD produced by gene targeting, and the evaluation of their efficacies in vivo."

Journal • Preclinical • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Quantitative Evaluation of Exon Skipping in Immortalized Muscle Cells in Vitro. (PubMed, Methods Mol Biol) - "This is the case with eteplirsen, an exon 51-skipping AO that is the first and only FDA-approved drug for DMD to date...Aside from allowing for the quantitative evaluation of candidate AOs based on their exon skipping efficiency and dystrophin protein rescue levels, these immortalized cells are stable, pure, easy to grow, and not subject to confounding by senescence-related issues. This procedure enables a more reliable screening of AOs prior to their entry in clinical trials and greatly facilitates the search for more efficacious candidate exon skipping AOs for DMD treatment."

Journal • Preclinical • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Evolution and Breakthroughs in Exon Skipping and Splice Modulation: From Inception to Clinical Success. (PubMed, Methods Mol Biol) - "The FDA has approved several AO therapies using exon skipping, including eteplirsen, viltolarsen, casimersen, and golodirsen for DMD and nusinersen for SMA. This chapter explores the early history, evolution, and clinical applications of AO-based splice modulation therapies, focusing on exon skipping, one of the most developed strategies."

Journal • Developmental Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Rare Diseases

Progress and Future Directions in Exon Skipping and Inclusion Therapies: The Landscape of Oligonucleotide-Based Genetic Medicine. (PubMed, Methods Mol Biol) - "Highlighting seminal developments, such as the approval of splice-switching ONs like eteplirsen for Duchenne Muscular Dystrophy and nusinersen for Spinal Muscular Atrophy, it underscores the critical role of these therapies in advancing patient-specific treatments. Commemorating the silver jubilee of the first ON therapy approval, this narrative not only celebrates the achievements but also critically examines the ongoing challenges and the imperative for sustained innovation and collaboration. The chapter aims to illuminate the path forward, emphasizing the need to harness the full promise of exon skipping and inclusion therapies in personalized genetic medicine."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Rare Diseases

Exon-Skipping Using Antisense Oligonucleotides for Laminin-Alpha2-Deficient Muscular Dystrophy. (PubMed, Methods Mol Biol) - "These findings support the theory that PMO entry into fibres is dependent on the developmental stage in myogenesis rather than on dystrophin-deficient muscle membranes, and recommend a platform for the future development of PMO-mediated therapies for a variety of muscular disorders, such as LAMA2-MD, that involve active muscle regeneration. Herein, we describe the methods for PMO transfection/injection and the evaluation of the efficacy of exon-skipping in the laminin-α2-deficient dy3K/dy3K mouse model both in vitro and in vivo."

Journal • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • LAMA2

Real-world phosphorodiamidate morpholino oligomer treatment patterns in Duchenne muscular dystrophy: a claims-based analysis. (PubMed, J Comp Eff Res) - "Male patients with ≥1 claim for a PMO approved for DMD in the US (eteplirsen, casimersen, golodirsen and viltolarsen) were included. In an analysis of administrative claims data, adherence to PMO treatment for DMD was high. For patients with a gap in PMO claims, most subsequently re-initiated treatment, indicating lower discontinuation rates than previously reported."

Journal • Real-world evidence • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

RNA Therapeutics: Focus on Antisense Oligonucleotides in the Nervous System. (PubMed, Biomol Ther (Seoul)) - "For instance, ASO therapies like nusinersen for spinal muscular atrophy and eteplirsen for Duchenne muscular dystrophy exemplify successful RNA therapeutic strategies. By addressing these challenges, RNA therapeutics hold immense potential to revolutionize treatment paradigms for neurological disorders. Looking forward, the future of RNA therapeutics in neurology appears promising but requires continued interdisciplinary collaboration and technological innovation."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Huntington's Disease • Infectious Disease • Movement Disorders • Muscular Dystrophy • Novel Coronavirus Disease • Rare Diseases

hfCas12Max: Engineered CRISPR Nuclease for Safer and Effective CGT (ASGCT 2025) - " After systemic delivery of a single all-in-one AAV vector that contained hfCas12Max CRISPR nuclease along with a gRNA targeting the splice donor (SD) site of the human DMD exon 51 in the Duchenne Muscular Dystrophy (DMD) mouse model, we observed efficient restoration of dystrophin expression... Our findings suggest that hfCas12Max CRISPR nuclease, with its robust editing activity and high specificity, is a promising tool for safer and more effective gene and cell therapy treatments. Synthetic guide RNAs and purified nuclease for hfCas12Max CRISPR nuclease are now readily available for CRISPR medicine developers through Synthego as Disease Focus of Abstract:Hepatitis"

Amyotrophic Lateral Sclerosis • CNS Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Muscular Dystrophy

CRISPR-hfCas12Max Genome Editing Therapy Demonstrates Preclinical Efficacy and Early Clinical Benefit in Duchenne Muscular Dystrophy (ASGCT 2025) - P=N/A | "Current therapies, including antisense oligonucleotides such as Casimersen (targeting exon 45) and Eteplirsen (targeting exon 51), achieve dystrophin restoration to < 2% of normal levels after 1-year with the burden of weekly administration. CRISPR/hfCas12Max-mediated single-cut genome editing therapy offers a transformative, "one-and-done" therapeutic approach for DMD. It provides significant advantages over existing treatments in safety, efficacy, and durability. The U.S. FDA has recognized HG302 with Orphan Drug Designation and Rare Pediatric Disease Designation, underscoring its potential to revolutionize DMD therapy and improve patient outcomes."

Preclinical • Cardiovascular • CNS Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Immunology • Inflammation • Muscular Dystrophy • Myositis • Pediatrics

Investigating the role of inflammatory cells in improving PMO delivery and exon-skipping efficiency in Duchenne muscular dystrophy (ASGCT 2025) - "To date, the U.S. Food and Drug Administration (FDA) has approved four exon-skipping ASO drugs (eteplirsen, gorodilsen, biltrasen, and casimelsen) for the treatment of DMD...We will further investigate the regulatory mechanism by which PMOs are transported to skeletal muscle. Disease Focus of Abstract:Muscular Dystrophy (all forms)"

Inflammatory cell • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

The Cost-Effectiveness of Eteplirsen vs. Standard of Care in Delaying the Progression of Duchenne Muscular Dystrophy (ISPOR 2025) - "Eteplirsen demonstrated clinical advantages in delaying the progression of DMD. However, its high cost restricts its cost-effectiveness relative to SoC. Further research is needed to generate current real-world utilities and costs associated with the use of eteplirsen among patients with DMD in the US, which can be leveraged to update this model."

Cost effectiveness • HEOR • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy