Therapeutic approaches for Duchenne muscular dystrophy

Roberts, Thomas C.; Wood, Matthew J. A.; Davies, Kay E.

doi:10.1038/s41573-023-00775-6

Cited by 42 publications

(13 citation statements)

References 206 publications

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“…A natural extension of this work will be to assess HDOs carrying DMD ON drugs. Splice correction of DMD transcripts in skeletal and cardiac muscle is critical for therapy of DMD (46) and has been notoriously difficult to achieve with current therapies (9).…”

Section: Discussionmentioning

confidence: 99%

Systemic delivery of a splice-switching oligonucleotide heteroduplex corrects splicing in central nervous system and muscle in spinal muscular atrophy mice

Halloy,

Ahlskog,

Wood

2024

Preprint

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Oligonucleotide therapeutics are an established class of drugs for the treatment of genetic disorders. Their clinical development is challenging, however, as they typically distribute poorly to extra-hepatic tissues after systemic injection. Here we tested the heteroduplex oligonucleotide (HDO) platform for systemic delivery of SMN2 splice-switching oligonucleotides of 2′-O-methoxyethyl phosphorothioate or phosphorodiamidate morpholino oligomer chemistries. We first showed that splice-switching HDO cargoes correct SMN2 splicing in cells derived from spinal muscular atrophy (SMA) patients, and validated extra-hepatic activity in spinal cord and muscle in a mouse model of SMA following systemic delivery. Our study raises prospects for delivery of nusinersen, the 2′-O-methoxylethyl phosphorothioate oligonucleotide therapy approved for SMA and currently delivered by intrathecal injection, by systemic injection exploiting the HDO chemistry platform. Our findings also suggest that oligonucleotide drugs lacking convincing in vivo efficacy in muscle tissue could be delivered effectively by the HDO technology.

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Section: Discussionmentioning

confidence: 99%

Systemic delivery of a splice-switching oligonucleotide heteroduplex corrects splicing in central nervous system and muscle in spinal muscular atrophy mice

Halloy,

Ahlskog,

Wood

2024

Preprint

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“…DMD is a fatal X-linked recessive disease affecting 1 out of 3500-5000 newborn males resulting from thousands of pathogenic mutations in the human X chromosome-linked DMD gene 22 . While there are thousands of documented clinical mutations, most DMD-causing mutations occur in a "hotspot" region encompassing exons 45 to 55 of the DMD gene, and skipping of exon 55 can provide therapeutic bene ts to approximately 2% of DMD patients 23 .…”

Section: Local Muscle Administration Of Cytosine Base Editor Atdcbe R...mentioning

confidence: 99%

Engineering TadA ortholog-derived cytosine base editor without motif preference and adenosine activity limitation

Zhou,

Li,

Dong

et al. 2024

Preprint

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The engineered TadA variants used in cytosine base editors (CBEs) present unique advantages, including a smaller size and fewer off-target effects compared to cytosine base editors that rely on natural deaminases. However, the current TadA variants demonstrate a preference for base editing in DNA with specific motif sequences and possess dual deaminase activity, acting on both cytosine and adenosine in adjacent positions, limiting their application scope. To address these issues, we employed TadA orthologs screening and multi sequence alignment (MSA)-guided protein engineering techniques to create a highly effective cytosine base editor (aTdCBE) without motif and adenosine deaminase activity limitations. Notably, the delivery of aTdCBE to a humanized mouse model of Duchenne muscular dystrophy (DMD) mice achieved robust exon 55 skipping and restoration of dystrophin expression. Our advancement in engineering TadA ortholog for cytosine editing enrich the base editing toolkits for gene-editing therapy and other potential applications.

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“…More recently, the CRISPR-Cas9 gene editing system has shown great promise to permanently restore the reading frame of the dystrophin gene, as demonstrated by numerous preclinical animal studies and cell culture studies. 3 …”

Section: Main Textmentioning

confidence: 99%

Base editing in humanized dystrophic mice

Zhang,

Zhou,

Han

2024

Molecular Therapy - Nucleic Acids

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Therapeutic approaches for Duchenne muscular dystrophy

Cited by 42 publications

References 206 publications

Systemic delivery of a splice-switching oligonucleotide heteroduplex corrects splicing in central nervous system and muscle in spinal muscular atrophy mice

Systemic delivery of a splice-switching oligonucleotide heteroduplex corrects splicing in central nervous system and muscle in spinal muscular atrophy mice

Engineering TadA ortholog-derived cytosine base editor without motif preference and adenosine activity limitation

Base editing in humanized dystrophic mice

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