{
  "abstract": "X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital neuromuscular disorder caused by mutations in the MTM1 gene. Affected infants typically present with severe hypotonia and respiratory failure, with up to 50% mortality in the first year of life. No approved disease-modifying therapies are currently available.At Great Ormond Street Hospital, through the Highly Specialised Congenital Myopathy Service, we have identified two ultra-rare deep intronic MTM1 mutations: one previously reported (c.1468-577A>G) and one novel (c.342+575C>G). Both mutations cause pseudo-exon inclusion and introduce premature stop codons, resulting in loss of MTM1 protein.We propose to develop two N-of-1 exon-skipping antisense oligonucleotide (ASO) therapies tailored to these mutations. By inducing skipping of the pseudo-exons, the ASOs aim to restore normal splicing and functional MTM1 protein expression.ASOs targeting both variants have already demonstrated effective pseudo-exon skipping and restoration of MTM1 protein in patient-derived fibroblasts. Building on these results, we will further optimise the ASO sequences and assess their efficacy and safety in MyoD-reprogrammed muscle cells and hepatocytes differentiated from patient-specific iPSCs, with the goal of demonstrating therapeutic benefit in both muscle and liver tissues.",
  "authors": [
    {
      "affiliations": [
        "UCL Queen Square Institute of Neurology, Neurodegenerative Diseases Department, London"
      ],
      "name": "Sara Aguti"
    },
    {
      "affiliations": [
        "Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine Research and Teaching Department, London"
      ],
      "name": "Y Shafi"
    },
    {
      "affiliations": [
        "UCL Queen Square Institute of Neurology, Neurodegenerative Diseases Department, London"
      ],
      "name": "J Mueller"
    },
    {
      "affiliations": [
        "Great Ormond Street Institute of Child Health, Developmental Neurosciences Research and Teaching Department, London"
      ],
      "name": "C Flett"
    },
    {
      "affiliations": [
        "Great Ormond Street Institute of Child Health, Developmental Neurosciences Research and Teaching Department, London"
      ],
      "name": "G Baranello"
    },
    {
      "affiliations": [
        "Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine Research and Teaching Department, London",
        "NIHR Great Ormond Street Hospital Biomedical Research Centre, London"
      ],
      "name": "H Zhou"
    },
    {
      "affiliations": [
        "UCL Queen Square Institute of Neurology, Neurodegenerative Diseases Department, London",
        "Great Ormond Street Institute of Child Health, Developmental Neurosciences Research and Teaching Department, London",
        "NIHR Great Ormond Street Hospital Biomedical Research Centre, London"
      ],
      "name": "F Muntoni"
    }
  ],
  "title": "P18 N-of-1 ASO therapeutic development for ultra-rare deep intronic mutations in X-linked myotubular myopathy",
  "uid": "a4b396ac-ffa8-55d1-a555-c2486798326d"
}