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Safety and biodistribution of XC001 (encoberminogene rezmadenovec) gene therapy in rats: a potential therapy for cardiovascular diseases

Gene Therapy volume 31, pages 45–55 (2024)Cite this article

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Abstract

Adenovirus-mediated gene therapy holds promise for the treatment of cardiovascular diseases such as refractory angina. However, potential concerns around immunogenicity and vector dissemination from the target injected tissue require evaluation. This study was undertaken to evaluate the safety and biodistribution of XC001, a replication-deficient adenovirus serotype 5 vector expressing multiple isoforms of human vascular endothelial growth factor (VEGF), following direct administration into normal rat myocardium. Animals received the buffer formulation or increasing doses of XC001 (1 × 107, 2.5 × 108 or 2.5 × 109 viral particles). Based on in-life parameters (general health, body weights, clinical pathology, serum cardiac troponin I, plasma VEGF, and gross necropsy), there were no findings of clinical concern. On Day 8, intramyocardial administration of XC001 was associated with dose-related, left ventricular myocardial inflammation at injection sites, resolving by Day 30. XC001 DNA was not detected in blood at any time but was present at Day 8 around the site of injection and to a much lesser extent in the spleen, liver, and lungs, persisting at low levels in the heart and spleen until at least Day 91. These findings demonstrate that intramyocardial injection of XC001 is supported for use in human studies.

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Fig. 1: Animal body weight over time.
Fig. 2: Myocardial and epicardial inflammation and fibrosis scores following XC001 intramyocardial injection.
Fig. 3: Representative hematoxylin-eosin-stained images showing inflammation and fibrosis in the left ventricular free wall of rats at Days 30 and 91 post XC001 injection.
Fig. 4: Cardiac serum troponin levels (cTnl) over time.
Fig. 5: Inflammation vs. cardiac serum troponin levels (cTnl) over time.
Fig. 6: XC001 DNA (copies/µg DNA) in tissues over time.

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Data availability

All data generated or analyzed during this study are included in this article and its supplementary information files.

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Acknowledgements

Editorial support was provided by Shereen Cynthia D'Cruz, Ph.D., of Certara Synchrogenix, and was funded by XyloCor Therapeutics.

Funding

Funding for this work was provided by XyloCor Therapeutics.

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Authors and Affiliations

  1. Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute and the Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada

    Duncan J. Stewart

  2. XyloCor Therapeutics, Wayne, PA, USA

    Albert Gianchetti, Dawn Byrnes, Howard C. Dittrich, Barb Thorne & Rickey R. Reinhardt

  3. Pharmaron (San Diego) Lab Services LLC, San Diego, CA, USA

    Linda L. Manza

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Contributions

AG, HCD, BT, LLM, and RRR contributed to the study conception and design. Material preparation, data collection, and analysis were performed by DJS, AG, DB, HCD, BT, LLM, and RRR. The first draft of the manuscript was written by DJS and RRR, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Duncan J. Stewart.

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Competing interests

AG, DB, HCD, and RRR were full-time employees of XyloCor Therapeutics when this work was done. DJS is a scientific advisory board member of XyloCor Therapeutics. The remaining authors declare no competing interests.

Ethics

Procedures involving the care or use of animals in this study were reviewed and approved by Absorption Systems California, LLC (ASC’s) Institutional Animal Care and Use Committee (IACUC) prior to the initiation of such procedures. During the study, the care and use of animals was conducted in accordance with the regulations of the USDA Animal Welfare Act (i.e., relevant sections of Section 9, Parts 1, 2, and 3, of the Code of Federal Regulations) and in compliance with ASC’s Animal Welfare Assurance (A4282-01) filed with the National Institutes of Health (NIH).

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Stewart, D.J., Gianchetti, A., Byrnes, D. et al. Safety and biodistribution of XC001 (encoberminogene rezmadenovec) gene therapy in rats: a potential therapy for cardiovascular diseases. Gene Ther 31, 45–55 (2024). https://doi.org/10.1038/s41434-023-00416-y

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