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Oxidative DNA damage drives apoptotic photoreceptor loss in NMNAT1-associated inherited retinal degeneration: a therapeutic opportunity
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  • Published: 02 April 2026

Oxidative DNA damage drives apoptotic photoreceptor loss in NMNAT1-associated inherited retinal degeneration: a therapeutic opportunity

  • Hanmeng Zhang1,
  • Kevin Valestil1,
  • Rossano M. Butcher1 &
  • …
  • Eric A. Pierce  ORCID: orcid.org/0000-0002-2354-41021 

Cell Death & Disease , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cell death
  • DNA adducts
  • Mechanisms of disease

Abstract

Early-onset inherited retinal degenerations (IRDs), such as Leber congenital amaurosis (LCA) caused by pathogenic variants in the NMNAT1 gene, lead to severe vision loss in children. Despite its ubiquitous expression, reduced NMNAT1 function primarily affects photoreceptor cells (PRs) of the retina, yet the mechanisms underlying their vulnerability remain incompletely understood. Here, we demonstrate that reduced NMNAT1 enzyme function due to the p.V9M mutation leads to DNA damage in PRs, characterized by the progressive accumulation of the oxidative DNA adduct 8-oxo-dG in Nmnat1V9M/V9M mutant mice. Cells with oxidative DNA damage also demonstrate DNA double-strand breaks, as evidenced by co-staining with antibodies to phosphorylated H2AX (γH2A.X). This DNA damage correlates with apoptosis-driven PR degeneration, as evidenced by caspase-9 activation and TUNEL staining in the PRs of the Nmnat1V9M/V9M mutant mice, while alternative cell death pathways such as necroptosis and parthanatos were not significantly activated. Treatment with the antioxidant N-acetylcysteine (NAC) reduced oxidative DNA damage and retinal immune responses, mitigated apoptosis, and preserved cone PRs. Longitudinal assessment via optical coherence tomography (OCT) and electroretinography (ERG) revealed sustained structural and functional protection of the retina in NAC-treated mice. These findings establish oxidative DNA damage as a key driver of PR degeneration in the Nmnat1V9M/V9M model and highlight NAC’s potential as a therapeutic strategy for NMNAT1-associated IRD and potentially other IRDs in which oxidative DNA damage contributes to disease pathogenesis.

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Data availability

All data relevant to the study are included in the article or uploaded as supplementary information. Source data are available upon reasonable request.

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Acknowledgements

The authors thank the Animal Facility staff for their help with animal care, and gratefully acknowledge Caitlin Keiper and Miele Macmillan for their technical assistance.

Funding

This work was supported by grants from the National Eye Institute (EY012910 to EAP), the Knights Templar Eye Foundation (2024-40 to HZ), and the Gavin R. Stevens Foundation.

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Authors and Affiliations

  1. Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA

    Hanmeng Zhang, Kevin Valestil, Rossano M. Butcher & Eric A. Pierce

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Contributions

EAP and HZ designed the study and prepared the manuscript. HZ performed the experiments and analyzed the data. KV contributed to mouse genotyping and OCT image analysis. RMB assisted with NAC and PBS intraperitoneal injections in mice.

Corresponding author

Correspondence to Eric A. Pierce.

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All experimental animal procedures were approved by the Animal Care and Use Committee of Massachusetts Eye and Ear (2021N000059) and were conducted in accordance with its guidelines and regulations.

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Zhang, H., Valestil, K., Butcher, R.M. et al. Oxidative DNA damage drives apoptotic photoreceptor loss in NMNAT1-associated inherited retinal degeneration: a therapeutic opportunity. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08680-7

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  • Received: 24 October 2025

  • Revised: 27 February 2026

  • Accepted: 13 March 2026

  • Published: 02 April 2026

  • DOI: https://doi.org/10.1038/s41419-026-08680-7

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