SRP-4055 / Sarepta Therap - LARVOL DELTA

Dataset of 16S rRNA and ITS gene amplicon sequencing of celery and parsley rhizosphere soils. (PubMed, BMC Genom Data) - "The most predominant taxonomic distribution of fungi at the phylum level includes Ascomycota and Mortierellomycota. The dataset includes raw sequence reads in FASTQ format (.fastq.gz), which have been deposited in the Sequence Read Archive (SRA) of the National Center for Biotechnology Information (NCBI) under the Bioproject Accession numbers; SRP540554 (16S rRNA) and SRP540675 (ITS)."

Journal

Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion. (PubMed, Skelet Muscle) - "Importantly, unlike the existing exon 55 deletion mice (which die by age 7 days), it survives beyond the first months and exhibits obvious signs of neuromuscular dysfunction. It thus provides a new, robust model for studying pathomechanisms and developing therapies for NEB related nemaline myopathy."

Journal • Preclinical • Myositis • NEB

Phenotypic variability in sisters with VPS13A disease (chorea-acanthocytosis) (PubMed, Ideggyogy Sz) - "Our findings support this terminological shift. Additionally, we first mentioned this synonymous mutation (NM_033305.3: c.7806G>C exon 55, p. Pro2602=) in the VPS13A gene, contributing to the understanding of this condition."

Journal • CNS Disorders • Epilepsy • Movement Disorders • Psychiatry

Early Cardiac Dysfunction in Duchenne Muscular Dystrophy: A Case Report and Literature Update. (PubMed, Int J Mol Sci) - "This case report presents a rare instance of early-onset cardiac involvement in a 3-year-old male with a confirmed deletion in exon 55 of the dystrophin gene...Genetic mechanisms and genotype-phenotype correlations related to cardiac involvement were reviewed, highlighting emerging therapies such as exon skipping, vamorolone, ifetroban, and rimeporide...While current DMD care standards improve survival, optimizing management through early intervention and novel therapies remains essential. Further research is needed to better understand genotype-phenotype correlations and improve cardiac outcomes for patients with DMD."

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

A Dual Diagnosis of Okur-Chung Neurodevelopmental Syndrome and Becker Muscular Dystrophy: Inquiry Into the Lower Limits of Neurodevelopmental Functioning Attributable to Muscular Dystrophy. (PubMed, Brain Behav) - "An FSIQ one standard deviation below these expected ranges should prompt screening for alternative causes of neurodevelopmental delays, and an FSIQ two standard deviations below these ranges should prompt broad-spectrum genetic testing."

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

Engineering TadA ortholog-derived cytosine base editor without motif preference and adenosine activity limitation. (PubMed, Nat Commun) - "Notably, the delivery of aTdCBE to a humanized mouse model of Duchenne muscular dystrophy (DMD) mice achieves robust exon 55 skipping and restoration of dystrophin expression. Our advancement in engineering TadA ortholog for cytosine editing enriches the base editing toolkits for gene-editing therapy and other potential applications."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Engineered Viral-Like Particles-Delivered Base Editor Ribonucleoprotein Complex Confers Efficient Base Editing in hiPSC and hiPSC-Derived Cardiomyocytes (ASGCT 2024) - "The eVLPs targeting the splice acceptor of exon 55 resulted in the efficient conversion of AG to GG (85.69% ± 0.58%) and enabled exon 55 skipping...In addition, eVLPs delivery rescued dystrophin expression in DMD hiPSC-derived cardiomyocytes, as examined by RT-PCR, Western blot, and immunofluorescence staining. These results highlight the great promise of eVLPs delivery of genome editor RNPs to facilitate hiPSC engineering."

Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Prevention of early-onset cardiomyopathy in Dmd exon 52-54 deletion mice by CRISPR-Cas9-mediated exon skipping. (PubMed, Mol Ther Methods Clin Dev) - "Here we employed CRISPR-Cas9 delivered intravenously by adeno-associated virus (AAV) vectors to restore functional dystrophin expression via excision or skipping of exon 55. Remarkably, our exon skipping approach completely prevented onset of the cardiac phenotype in treated mice up to 12 weeks. Thus, our results demonstrate that intravenous delivery of a single-cut CRISPR-Cas9-mediated exon skipping therapy can prevent heart dysfunction in DMD in vivo."

Journal • Preclinical • Cardiomyopathy • Cardiovascular • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Immunology • Muscular Dystrophy

Base Editing Correction of DMD in Human iPSC-Derived Cardiomyocytes and Dystrophic Mice (ASGCT 2023) - "Co-transfection of ABE and a guide RNA (gRNA) targeting the splice acceptor led to efficient conversion of AG to GG (35.9% ± 5.7%) and enabled exon 55 skipping...Moreover, we demonstrated the efficiency of inducing exons 6, 7, 8, 43, 44, 46, and 53 skipping in iCMs. These results highlight base editing with iABE-NGA as a promising therapeutic approach for DMD."

Preclinical • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Correction of DMD in human iPSC-derived cardiomyocytes by base-editing-induced exon skipping. (PubMed, Mol Ther Methods Clin Dev) - "Transfection of ABE and a guide RNA (gRNA) targeting the splice acceptor led to efficient conversion of AG to GG (35.9% ± 5.7%) and enabled exon 55 skipping...Moreover, we designed gRNAs to target the splice sites of exons 6, 7, 8, 43, 44, 46, and 53 in the mutational hotspots and demonstrated their efficiency to induce exon skipping in iCMs. These results highlight the great promise of ABE-mediated exon skipping as a promising therapeutic approach for DMD."

Journal • Cardiomyopathy • Cardiovascular • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Identification of immune-related features involved in Duchenne muscular dystrophy: A bidirectional transcriptome and proteome-driven analysis. (PubMed, Front Immunol) - "In addition, three genes (ATP6AP2, CTSS, and VIM) showed excellent diagnostic performance on discriminating DMD in GSE1004, GSE3307, GSE6011 and GSE38417 datasets (all AUC > 0.8), which is validated in patients (10 DMD vs. 10 controls), DMD with exon 55 mutations, mdx mouse, and nomogram model. Taken together, ATP6AP2, CTSS, and VIM play important roles in the inflammatory response in DMD, which may serve as diagnostic biomarkers and therapeutic targets."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Immunology • Inflammation • Muscular Dystrophy • ATP6AP2 • CTSS • MIR130A • MIR152 • MIR17 • RELA • TFAP2A • TFAP2C

Transformation from polycythemia vera to acute promyelocytic leukemia: Case report and literature review. (PubMed, Medicine (Baltimore)) - "Polycythemia vera can transform into acute promyelocytic leukemia; therefore, it is important to review bone aspiration and other tests to perform a comprehensive assessment and monitor the disease status, to detect disease progression and intervene early when it transforms into acute promyelocytic leukemia."

Journal • Review • Acute Promyelocytic Leukemia • Chronic Eosinophilic Leukemia • Fatigue • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • JAK2 • JAK3 • RARA • TMB • WT1

Correction of DMD in Human iPSC-Derived Cardiomyocytes by Base Editing-Induced Exon Skipping (ASGCT 2022) - "Transfection of ABE and a guide RNA (gRNA) targeting the splice acceptor enabled efficient exon 55 skipping (Fig.1C), restored dystrophin expression (Fig.1 E,F) and improved the contraction amplitude in DMD hiPSC-derived cardiomyocytes (iCMs) (Fig.1G)...Moreover, we designed gRNAs to target the splice sites of exons 6, 8, 43, 45 and 50, and demonstrated that they can also induce exon skipping in WT iCMs (Fig.1H). These results highlight the great promise of ABE-mediated exon skipping as a novel therapeutic approach for DMD cardiomyopathy."

Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Duchenne Muscular Dystrophy • Genetic Disorders • Heart Failure • Muscular Dystrophy • NANOG • POU5F1

Morpholino Oligomer-Induced Dystrophin Isoforms to Map the Functional Domains in the Dystrophin Protein. (PubMed, Mol Ther Nucleic Acids) - "However, there is a lack of genotype-phenotype correlations downstream of DMD exon 55, as deletions in this region are rare and most single exon deletions would disrupt the reading frame. Here, we induced "Becker muscular dystrophy-like" in-frame dystrophin isoforms in vivo by intraperitoneal injection of peptide-conjugated phosphorodiamidate morpholino oligomers targeting selected exons. The dystrophin isoform encoded by the transcript lacking exons 56+57 appears to be more functional than that encoded by the 58+59-deleted transcript, as determined by higher dystrophin expression, stabilized β-dystroglycan, and less severe dystrophic pathology, indicating some potential for the strategy to address Duchenne-causing mutations affecting these exons."

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

Triggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism. (PubMed, Nat Commun) - "We created a mouse model with a missense mutation p.Ser6366Ile and a deletion of NEB exon 55, the Compound-Het model that resembles typical NM...X-ray diffraction revealed that the actin filament is twisted with a larger radius, that tropomyosin and troponin behavior is altered, and that the myofilament spacing is increased. The unique disease mechanism of nebulin-based typical NM reveals novel therapeutic targets."

Journal • Myositis