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Peer-reviewedCC BY-NCScience Advances

A bifunctional actuator to correct loss-of-function deficits in cardiac voltage-gated sodium channels

  • Lucile Fossier1
  • Marc Yehya1
  • Richard Z. Zhuang2
  • Sri Karthika Shanmugam1
  • Ryan Mahling1
  • Timothy Cho1
  • Audrey Kochiss1
  • Allen L. Hsu1
  • Sandra B. Gabelli3
  • Gordana Vunjak-Novakovic2,4,5
  • Henry M. Colecraft1,6
  • Manu Ben-Johny1
6 affiliations
  1. 1Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.
  2. 2Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
  3. 3Discovery Chemistry, Merck Research Laboratory, Merck and Co. Inc., West Point, PA 19486, USA.
  4. 4Department of Medicine, Columbia University, New York, NY 10032, USA.
  5. 5College of Dental Medicine, Columbia University, New York, NY 10032, USA.
  6. 6Department of Pharmacology and Molecular Therapeutics, Columbia University, New York, NY 10032, USA.
Open at sourceDOICite

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.

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Cite

BibTeXRIS
BibTeX
@article{fossier2026bifunctional,
  title = {{A bifunctional actuator to correct loss-of-function deficits in cardiac voltage-gated sodium channels}},
  author = {Lucile Fossier and Marc Yehya and Richard Z. Zhuang and Sri Karthika Shanmugam and Ryan Mahling and Timothy Cho and Audrey Kochiss and Allen L. Hsu and Sandra B. Gabelli and Gordana Vunjak-Novakovic and Henry M. Colecraft and Manu Ben-Johny},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeb2110},
  url = {https://www.science.org/doi/10.1126/sciadv.aeb2110},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - A bifunctional actuator to correct loss-of-function deficits in cardiac voltage-gated sodium channels
AU  - Lucile Fossier
AU  - Marc Yehya
AU  - Richard Z. Zhuang
AU  - Sri Karthika Shanmugam
AU  - Ryan Mahling
AU  - Timothy Cho
AU  - Audrey Kochiss
AU  - Allen L. Hsu
AU  - Sandra B. Gabelli
AU  - Gordana Vunjak-Novakovic
AU  - Henry M. Colecraft
AU  - Manu Ben-Johny
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.aeb2110
UR  - https://www.science.org/doi/10.1126/sciadv.aeb2110
AB  - 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.
SN  - 2375-2548
ER  -