DMD exon 45 skipping program / Wave Life Sciences - LARVOL DELTA

Association Between DMD Genotype and Neurodevelopmental Concerns in Childhood-Onset Dystrophinopathy Using Population-Based Surveillance Data (AAN 2025) - "We defined proximal DMD variants as those located 5' to DMD exon 45, and distal DMD variants as those located 3' of and including DMD exon 45...There was no statistically significant association between the burden of neurodevelopmental concerns and DMD genotype in the MDSTARnet data but dystrophinopathy individuals with variants located in DMD exons 63 to 79 had statistically significant higher frequencies of ID, GDD, and multiple neurodevelopmental concerns."

Clinical • Neurodevelopmental • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • Autism Spectrum Disorder • CNS Disorders • Cognitive Disorders • Developmental Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Mental Retardation • Mood Disorders • Muscular Dystrophy • Obsessive-Compulsive Disorder • Psychiatry

In Vitro Efficacy of an Endosomal Escape Vehicle (EEV™) – DMD Exon 45 Skipping Oligonucleotide Conjugate in DMD Patient-Derived Skeletal and Cardiac Muscle Cells (New Directions 2024) - No abstract available

Preclinical • Duchenne Muscular Dystrophy

Development of Deaminase-Free Base Editors by Engineering DNA Glycosylases (ASGCT 2024) - "We then co-injected the gTBEv3 mRNA and sgRNA targeting the SD site of DMD exon 45 into zygotes of humanized DMD mice... Our findings indicate that certain DNA glycosylases could be engineered into enzymes that selectively excise specific nucleotide bases and be applied to develop novel base editors with various features. The gBE novel base editors provide additional options for the sites that dBEs could not target, largely expanding the targeting scope of base editors."

PCSK9

AID-Seq High-Throughput sgRNA Screening Facilitates FrCas9-Mediated Large Fragment Deletion of DMD Exons 45-55 (ASGCT 2024) - "In contrast, SpCas9 showed significantly higher numbers of off-target sites and reads, with multiple off-targets detected per sgRNA (Fig 1F-H).The screened FrCas9 sgRNA can efficiently and accurately delete the DMD exon 45-55 large fragment... These results collectively point to the enhanced specificity and efficiency of FrCas9 in the context of large genomic edits, which is crucial for DMD therapeutic applications.Plain Language Summary: Using our previously established AID-seq high-throughput sgRNA screening strategy to fully compare the on-target efficiency and off-target effects of FrCas9 and SpCas9, and screen out safe and efficient sgRNAs that target the DMD intron 44 and 55. Further paired cutting of two sgRNAs was performed to confirm its precise large fragment deletion efficiency, laying the foundation for DMD gene therapy."

Duchenne Muscular Dystrophy • Gene Therapies

Targeting Duchenne muscular dystrophy by skipping DMD exon 45 with base editors. (PubMed, Mol Ther Nucleic Acids) - "We now demonstrate that CRISPR-SKIP can be adapted to correct some forms of Duchenne muscular dystrophy by disrupting the splice acceptor in human DMD exon 45 with high efficiency, which enables open reading frame recovery and restoration of dystrophin expression. We also demonstrate that AAV-delivered split-intein base editors edit the splice acceptor of DMD exon 45 in cultured human cells and in vivo, highlighting the therapeutic potential of this strategy."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

CRISPR Base Editing Approach to Treat Duchenne Muscular Dystrophy by Skipping DMD Exon 45 (ASGCT 2023) - "More importantly, split base editors delivered by AAV in vivo following intramuscular or systemic injections efficiently edited the splice acceptor of DMD exon 45. In summary, this work describes a novel exon skipping strategy that relies on base editors to enable efficient skipping of exon 45 in the dystrophin gene as well as a platform for in vivo delivery of base editing tools for correcting Duchenne muscular dystrophy."

Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Dystrophinopathy phenotypes and modifying factors in DMD exon 45-55 deletion. (PubMed, Ann Neurol) - "We confirmed del45-55 segregates a high proportion of benign phenotypes, severe cases, and isolated cardiac and cognitive presentations. Although some influence of the intronic breakpoint position and the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic variability remain largely unresolved."

Journal • Alzheimer's Disease • Cognitive Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • SPP1

[VIRTUAL] Characterization of a new Duchenne Muscular Dystrophy rat model with an outofframe deletion of exon 45 (ESGCT 2021) - "Here we present a DMD rat model generated by CRISPR/Cas9 excision of Dmd exon 45, the most common single exon deletion in DMD patients...This rat model could offer new insights into the exon splicing machinery of the DMD gene and new possible therapeutic targets. In addition to being a muscular dystrophy model, our DMD model can be useful for a better understanding of the involvement of dystrophin in brain function."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Immunology • Inflammation • Mood Disorders • Muscular Dystrophy • Psychiatry

[VIRTUAL] Homology-Independent Targeted Integration for Correction of DMD Distal Hotspot Mutations (ASGCT 2021) - "Next, we packaged the HITI gene editing system into AAV and tested it in patient-derived myogenic cells and via systemic delivery into a humanized mouse model of DMD exon 45 deletion. This work provides proof of concept data in support of a HITI gene editing approach to replace exons 41 - 55 that could benefit ~37% of DMD patients with mutations that lie between intron 40 and 55."

Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Longitudinal Evaluation of Working Memory in Duchenne Muscular Dystrophy. (PubMed, J Clin Med) - "Developmental growth modeling showed that subjects with nmDMD mutations upstream of DMD exon 30, upstream of DMD exon 45, and upstream of DMD exon 63 appeared to make better gains in working memory than subjects with mutations downstream of DMD exon 30, downstream of DMD exon 45, and downstream of DMD exon 63...Maturation in cognition was seen over a 48-week period. The developmental trajectory of working memory in this cohort was influenced by DMD mutation location."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Relationships between DMD mutations and neurodevelopment in dystrophinopathy. (PubMed, Neurology) - "Our data support evidence for a relationship between neurodevelopmental concerns and DMD mutation. A longitudinal assessment of developmental trajectory is necessary to evaluate how specific DMD mutations affect brain function."

Journal