{
  "abstract": "A definitive molecular diagnosis is essential for the clinical management of rare genetic diseases (RGDs), guiding prognosis, genetic counseling, and therapeutic development. RNA-based therapeutics have emerged as promising strategies for RGDs owing to their ability to modulate gene expression and splicing. Here, we establish an integrated and scalable pipeline from variant discovery to RNA-based therapy in inherited retinal diseases (IRDs). Genome sequencing identified three cryptic variants in known IRD genes. Two novel deep intronic variants in SDCCAG8 were characterized by RT-PCR to induce pseudoexon inclusion. In addition, a previously described deep intronic variant in CEP290 was detected and reproduced on patient-derived fibroblasts, confirming aberrant splicing. A third family carrying the recurrent ABCA4 c.768G>T silent variant was included to corroborate the translational strength of our pipeline and to provide an additional model for RNA-based therapeutic correction. We designed and tested 16 splice-switching antisense oligonucleotides (ssASOs) in patient-derived fibroblasts, HeLa cells transfected with mutant minigenes, and, when available, human induced pluripotent stem cell (hiPSC)-derived retinal organoids. For each variant, at least one ssASO successfully improved normal splicing and increased gene expression in patient-derived models. Overall, this study validates an innovative end-to-end translational workflow and highlights how molecular diagnosis can directly drive the development of personalized RNA-based therapies.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy; IRCCS Mondino Foundation, Neurogenetics Research Centre, 27100 Pavia, Italy",
    "Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Scuola Superiore Meridionale (School of Advanced Studies), Genomics and Experimental Medicine Program (GEM), Naples, Italy",
    "Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy",
    "Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy",
    "Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy",
    "IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy",
    "Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy",
    "IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy",
    "Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy; Medical Genetics Unit, IRCCS San Matteo Foundation, Pavia, Italy",
    "UOSD Medical Genetics and Cardiomyology, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Naples, Italy; Medical Genetics, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy",
    "Medical Genetics, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy; Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy",
    "Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; UOSD Medical Genetics and Cardiomyology, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Naples, Italy; Medical Genetics, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy",
    "Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy",
    "Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy; IRCCS Mondino Foundation, Neurogenetics Research Centre, 27100 Pavia, Italy; Corresponding author: Elisa Giorgio, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Mariia Zadorozhna"
    },
    {
      "affs": [
        1
      ],
      "name": "Simona Rossi"
    },
    {
      "affs": [
        2
      ],
      "name": "Erika Tenderini"
    },
    {
      "affs": [
        3
      ],
      "name": "Ilaria Brentari"
    },
    {
      "affs": [
        4
      ],
      "name": "Anna Basile"
    },
    {
      "affs": [
        4
      ],
      "name": "Giulia Pezzin"
    },
    {
      "affs": [
        4
      ],
      "name": "Rebecca Venturini"
    },
    {
      "affs": [
        5
      ],
      "name": "Federica Isidori"
    },
    {
      "affs": [
        6
      ],
      "name": "Elena Luppi"
    },
    {
      "affs": [
        7
      ],
      "name": "Emanuele Panza"
    },
    {
      "affs": [
        8
      ],
      "name": "Fabio Sirchia"
    },
    {
      "affs": [
        0
      ],
      "name": "Elena Rossi"
    },
    {
      "affs": [
        9
      ],
      "name": "Mariateresa Zanobio"
    },
    {
      "affs": [
        10
      ],
      "name": "Marianthi Karali"
    },
    {
      "affs": [
        5
      ],
      "name": "Tommaso Pippucci"
    },
    {
      "affs": [
        9
      ],
      "name": "Giulio Piluso"
    },
    {
      "affs": [
        3
      ],
      "name": "Michela Alessandra Denti"
    },
    {
      "affs": [
        5
      ],
      "name": "Marco Seri"
    },
    {
      "affs": [
        11
      ],
      "name": "Sandro Banfi"
    },
    {
      "affs": [
        12
      ],
      "name": "Ivana Trapani"
    },
    {
      "affs": [
        13
      ],
      "name": "Elisa Giorgio"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fy5gasmh6drvz.bib",
  "cited_by": 0,
  "doi": "10.1016/j.omtn.2026.103139",
  "fulltext_url": "http://www.sciencedirect.com/science/article/pii/S2162253126003100",
  "id": "fy5gasmh6drvz",
  "issns": [
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  "landing_url": "https://doi.org/10.1016/j.omtn.2026.103139",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
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      "lcc",
      "RM1-950"
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      "openalex",
      "1312|RNA Research and Splicing"
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  "openalex": "W7221777672",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-03",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/fy5gasmh6drvz.ris",
  "sources": [
    {
      "first_seen": "2026-11-03T14:21:25Z",
      "native_id": "031e59e9eac14e93a56a4c56b474b945",
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      "url": "https://doi.org/10.1016/j.omtn.2026.103139"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA Research and Splicing",
      "subfield": "molecular-biology"
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  "title": "Targeting cryptic splicing variants in",
  "title_text": "Targeting cryptic splicing variants in",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T14:20:21Z",
  "url": "https://research.draconitic.com/paper/fy5gasmh6drvz",
  "venue": "Molecular Therapy: Nucleic Acids",
  "versions": []
}