{
  "abstract": "Despite their emerging prominence, ion channelopathies have remained challenging to correct, as ion channel dysfunction linked to disease is multifaceted, involving changes in activity and/or localization. Yet, current corrective strategies typically focus on restoring only one aspect leading to incomplete efficacy. Here, focusing on the voltage-gated sodium channel, Na V 1.5, whose dysfunction is linked to life-threatening cardiac arrhythmias, we develop a genetically encoded bifunctional actuator as a proof-of-concept molecular strategy to reverse pathophysiological changes in channel function. Specifically, we engineer a high affinity nanobody targeting Na V 1.5 with two moieties: (i) a peptide that restores proper inactivation and (ii) a linkage-specific deubiquitinase that promotes surface-membrane localization. Functional validation in heterologous systems and in human and mouse cardiomyocytes demonstrated restoration of Na V 1.5 trafficking and/or gating. In all, this approach shows promise for reversing molecular deficits observed with Na V channelopathies and provides a framework to engineer multifunctional modulators targeting ion channelopathies.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.",
    "Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.",
    "Discovery Chemistry, Merck Research Laboratory, Merck and Co. Inc., West Point, PA 19486, USA.",
    "Department of Medicine, Columbia University, New York, NY 10032, USA.",
    "College of Dental Medicine, Columbia University, New York, NY 10032, USA.",
    "Department of Pharmacology and Molecular Therapeutics, Columbia University, New York, NY 10032, USA."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Lucile Fossier",
      "orcid": "0000-0002-1837-9093"
    },
    {
      "affs": [
        0
      ],
      "name": "Marc Yehya",
      "orcid": "0000-0003-4098-5580"
    },
    {
      "affs": [
        1
      ],
      "name": "Richard Z. Zhuang",
      "orcid": "0000-0002-3959-5094"
    },
    {
      "affs": [
        0
      ],
      "name": "Sri Karthika Shanmugam",
      "orcid": "0000-0002-1467-401X"
    },
    {
      "affs": [
        0
      ],
      "name": "Ryan Mahling",
      "orcid": "0000-0002-4590-2724"
    },
    {
      "affs": [
        0
      ],
      "name": "Timothy Cho",
      "orcid": "0009-0002-5809-548X"
    },
    {
      "affs": [
        0
      ],
      "name": "Audrey Kochiss",
      "orcid": "0009-0007-4800-9855"
    },
    {
      "affs": [
        0
      ],
      "name": "Allen L. Hsu",
      "orcid": "0000-0003-2065-3802"
    },
    {
      "affs": [
        2
      ],
      "name": "Sandra B. Gabelli",
      "orcid": "0000-0003-1205-5204"
    },
    {
      "affs": [
        1,
        3,
        4
      ],
      "name": "Gordana Vunjak-Novakovic",
      "orcid": "0000-0002-9382-1574"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Henry M. Colecraft",
      "orcid": "0000-0002-2340-8899"
    },
    {
      "affs": [
        0
      ],
      "name": "Manu Ben-Johny",
      "orcid": "0000-0002-5645-0815"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9z10w830cfder.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aeb2110",
  "fulltext_url": null,
  "id": "9z10w830cfder",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/10.1126/sciadv.aeb2110",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2705|Cardiac electrophysiology and arrhythmias"
    ]
  ],
  "openalex": "W7221115799",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-09",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/9z10w830cfder.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:41Z",
      "native_id": "10.1126/sciadv.aeb2110",
      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aeb2110"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2705|Cardiac electrophysiology and arrhythmias",
      "subfield": "cardiovascular"
    }
  ],
  "title": "A bifunctional actuator to correct loss-of-function deficits in cardiac voltage-gated sodium channels",
  "title_text": "A bifunctional actuator to correct loss-of-function deficits in cardiac voltage-gated sodium channels",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:41Z",
  "url": "https://research.draconitic.com/paper/9z10w830cfder",
  "venue": "Science Advances",
  "versions": []
}