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Biomedicines
Volume 13
Issue 9
10.3390/biomedicines13092052
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

In Vivo Characterization of ONL1204, a Small Peptide Inhibitor of the Fas Receptor, as a Potential Neuroprotective Therapy for Geographic Atrophy and Dry Age-Related Macular Degeneration

by
Andrew J. Kocab
1,*,
Marisol Cano
2,
Marianna Bacellar-Galdino
3,
Jeffrey A. Jamison
4,
William J. Brock
5,
David N. Zacks
1,6 and
James T. Handa
2,*
1
ONL Therapeutics, Inc., Ann Arbor, MI 48104, USA
2
Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD 21287, USA
3
Altasciences, Scott Township, PA 18411, USA
4
Ocular Consultants, Inc., Livonia, MI 48154, USA
5
Brock Scientific Consulting, LLC, Hilton Head, SC 29926, USA
6
Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA
*
Authors to whom correspondence should be addressed.
Biomedicines 2025, 13(9), 2052; https://doi.org/10.3390/biomedicines13092052
Submission received: 23 July 2025 / Revised: 14 August 2025 / Accepted: 19 August 2025 / Published: 22 August 2025
(This article belongs to the Special Issue Advances in Therapeutics for Retinal Degeneration)
Versions Notes

Abstract

Background: Age-related macular degeneration (AMD) is a major cause of irreversible vision loss in the developed world, and the approved products for geographic atrophy (GA), a late-stage form of dry AMD, have shown limited efficacy and require frequent administration. Therefore, longer-lasting therapies with improved efficacy would be a welcome addition to AMD treatment. One potential therapeutic is ONL1204, a small peptide inhibitor of the Fas receptor that has prevented cell death and inflammation in retinal disease models. This study characterizes the pharmacokinetics (PK) and durability of protection conferred by ONL1204. Methods: Ocular pharmacokinetic profiles were generated over 3 months in rabbit and minipig following a single intravitreal (IVT) injection of ONL1204 at multiple doses. Ocular pharmacodynamics were evaluated in two models: a rabbit model using a single IVT injection of ONL1204 with a delayed sodium iodate challenge coupled with fluorescein angiography to quantify RPE loss, and a chronic mouse model that reflects key features of dry AMD disease pathology to assess the efficacy of repeat IVT administrations of ONL1204. Results: ONL1204 had prolonged residence in the ocular tissues of rabbit and minipig, with a vitreous humor half-life of over 100 days. ONL1204 demonstrated significant protection of the retinal pigment epithelium (RPE) in the rabbit sodium iodate model. In the chronic mouse model, two administrations of ONL1204 preserved RPE morphology, reduced caspase-8 activity, and decreased inflammation. Conclusions: These data represent key characteristics of ONL1204, highlighting its clinical potential as a therapeutic for chronic retinal diseases, including GA.
Keywords: age-related macular degeneration; geographic atrophy; neuroprotection; Fas; CD95; animal models age-related macular degeneration; geographic atrophy; neuroprotection; Fas; CD95; animal models

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MDPI and ACS Style

Kocab, A.J.; Cano, M.; Bacellar-Galdino, M.; Jamison, J.A.; Brock, W.J.; Zacks, D.N.; Handa, J.T. In Vivo Characterization of ONL1204, a Small Peptide Inhibitor of the Fas Receptor, as a Potential Neuroprotective Therapy for Geographic Atrophy and Dry Age-Related Macular Degeneration. Biomedicines 2025, 13, 2052. https://doi.org/10.3390/biomedicines13092052

AMA Style

Kocab AJ, Cano M, Bacellar-Galdino M, Jamison JA, Brock WJ, Zacks DN, Handa JT. In Vivo Characterization of ONL1204, a Small Peptide Inhibitor of the Fas Receptor, as a Potential Neuroprotective Therapy for Geographic Atrophy and Dry Age-Related Macular Degeneration. Biomedicines. 2025; 13(9):2052. https://doi.org/10.3390/biomedicines13092052

Chicago/Turabian Style

Kocab, Andrew J., Marisol Cano, Marianna Bacellar-Galdino, Jeffrey A. Jamison, William J. Brock, David N. Zacks, and James T. Handa. 2025. "In Vivo Characterization of ONL1204, a Small Peptide Inhibitor of the Fas Receptor, as a Potential Neuroprotective Therapy for Geographic Atrophy and Dry Age-Related Macular Degeneration" Biomedicines 13, no. 9: 2052. https://doi.org/10.3390/biomedicines13092052

APA Style

Kocab, A. J., Cano, M., Bacellar-Galdino, M., Jamison, J. A., Brock, W. J., Zacks, D. N., & Handa, J. T. (2025). In Vivo Characterization of ONL1204, a Small Peptide Inhibitor of the Fas Receptor, as a Potential Neuroprotective Therapy for Geographic Atrophy and Dry Age-Related Macular Degeneration. Biomedicines, 13(9), 2052. https://doi.org/10.3390/biomedicines13092052

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