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Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results

Nature Medicine volume 30, pages 443–454 (2024)Cite this article

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Abstract

Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884.

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Fig. 1: Pathways of cellular senescence are triggered in the diabetic retina.
Fig. 2: Sustained high glucose triggers DNA damage and cellular senescence in ECs.
Fig. 3: Targeted elimination of senescent cells reduces diabetes-induced vascular leakage and preserves retinal function.
Fig. 4: Intravitreal injection of UBX1325 in patients with DME.

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Data availability

Requests for additional information, reagents or material resources should be addressed to P.S. Sequencing data from STZ-treated mouse retinas have been deposited in NCBI’s Gene Expression Omnibus under accession number GSE211583. Datasets used to perform single-cell transcriptomic analyses on mouse diabetic retinas were previously published and are publicly available under the accession number GSE178121. Datasets used to perform bulk transcriptomic analyses on rat diabetic retinas were previously published and are publicly available under the accession number GSE20886. All information on materials and reagents is provided in Supplementary Information. All clinical data have been provided in the paper in the form of figures, in the text or in Supplementary Information (including the clinical trial protocol, STROBE checklist and the statistical analysis plan). Additional requests for clinical data should be addressed to the corresponding author and may be provided upon reasonable request. Source data are provided with this paper.

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Acknowledgements

P.S. holds the Wolfe Professorship in Translational Research, a Canada Research Chair in Retinal Cell Biology as well as the Fonds de Recherche en Ophtalmologie de l’Université de Montréal Endowed Chair. S.C.-G. holds a fellowship from the Fonds de Recherche du Québec - Santé (FRQ-S) and the Montreal Diabetes Research Center. This work was supported by UNITY Biotechnology. Other funding was provided from operating grants to P.S. from Diabetes Canada (DI-3-18-5444-PS), the Canadian Institutes of Health Research (Foundation grant 353770), The Alcon Research Institute Senior Investigator Award and The Heart and Stroke Foundation of Canada (G-16-00014658) and BrightFocus Foundation (M2022015I). Additional support was provided by the Fonds de Recherche en Ophtalmologie de l’Université de Montréal (FROUM), the Réseau en Recherche en Santé de la Vision (RRSV) and the FRQ-S/RRSV-funded Single-Cell Academy. We thank V. Guber for the management of the mouse colony, the research assistants at the animal facilities, and M. Sergeev at the microscope core facilities of the Hospital Maisonneuve-Rosemont Research Center for all their technical support throughout the duration of this project. We also thank H. Findlay and G. Mawambo for the technical assistance provided, and B. Larrivée for reagents.

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  1. Sergio Crespo-Garcia

    Present address: École d’optométrie, University of Montreal, Montreal, Quebec, Canada

Authors and Affiliations

  1. Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada

    Sergio Crespo-Garcia, Frédérik Fournier, Roberto Diaz-Marin, Guillaume Blot, Rana Rizk, Manuel Buscarlet, Masayuki Hata, Frédérick A. Mallette & Przemyslaw Sapieha

  2. Department of Ophthalmology, Centre Universitaire d’Ophtalmologie (CUO-HMR) Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada

    Roberto Diaz-Marin, Ikhlas Hafiane, Agnieszka Dejda, Rachel Juneau, Sarah Chorfi, Flavio A. Rezende, Ariel M. Wilson & Przemyslaw Sapieha

  3. UNITY Biotechnology, South San Francisco, CA, USA

    Sharon Klier, Derek Ragusa, Lauren Masaki, Priyanka Patel, Pedro J. Beltran, Alex Nguyen, Lynne Sullivan, Jason Damiano, Nathaniel E. David, Anirvan Ghosh, Pamela R. Tsuruda, Jamie Dananberg & Przemyslaw Sapieha

  4. Departments of Pediatrics Ophthalmology, and Pharmacology, Centre Hospitalier Universitaire Sainte Justine Research Center, Montreal, Quebec, Canada

    Gael Cagnone & Jean-Sebastien Joyal

  5. Department of Medicine, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada

    Frédérick A. Mallette

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Contributions

P.S., S.C.-G., J. Dananberg, A.G. and L.S. designed the study with contribution from P.R.T.; S.C.-G., F.F., R.D.-M., G.C., G.B., I.H., R.R., R.J. and P.P. performed research; F.A.R. provided human specimens; S.C.-G., F.F., R.D.-M., G.C., G.B., R.R., M.B., A.D., S.C., P.P., P.R.T., P.J.B. and P.S. analyzed data; S.C.-G. prepared the figures; P.S. and S.C.-G. wrote the paper with contributions from P.R.T., A.G., F.A.M., S.K., D.R., J. Dananberg, P.J.B., A.M.W. and M.H. All authors revised and approved the submitted version of the paper.

Corresponding author

Correspondence to Przemyslaw Sapieha.

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Competing interests

P.S., J. Dananberg, A.G., L.S. and A.N. are executives at UNITY Biotechnology. N.D. is the founder of UNITY Biotechnology. S.K., D.R., L.M., P.P., P.J.B., A.N., J.D., L.S. and P.R.T. were employees of UNITY Biotechnology during the time this project was developed and hold shares in the company. S.C.-G., R.D.-M., F.F., G.C., A.D., A.M.W. and J.-S.J. have contract work with UNITY Biotechnology. The other authors declare no competing interests.

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Nature Medicine thanks William Keyes and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Michael Basson, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Table 1 DME and nAMD patients enrolled in NCT04537884 and treated with UBX1325 (demographics).
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Supplementary information

Supplementary Information

Supplementary Fig. 1. mRNA expression of OCLN and CDH5 in glucose-treated HRMECs. Relative to Fig. 2. Supplementary Fig. 2. UBX1967 selectively induces apoptosis in radiation-induced senescent human retina microvascular ECs. Supplementary Fig. 3. UBX1967 selectively induces apoptosis in high-glucose-induced senescent human retina microvascular ECs. Supplementary Fig. 4. Effect of a single dose of UBX1325 in patients with nAMD. Relative to Fig. 4. Supplementary Table 1. Human vitreous patient data Supplementary Table 2. Human histology patient data Supplementary Table 3. UBX0601 pharmacokinetics in vitro. Supplementary Table 4. Ocular TEAEs by severity of all patients administered UBX1325 (DME + nAMD patients). Supplementary Table 5. Summary of BCVA in DME patients (course of 24 weeks). Supplementary Table 6. Primary antibodies list. Supplementary Table 7. RT–qPCR primer list. Supplementary Note 1. Clinical trial protocol. Supplementary Note 2. Clinical trial STROBE checklist. Supplementary Note 3. Clinical trial statistical analysis plan.

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Source data

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Unprocessed western blots (combined file).

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Crespo-Garcia, S., Fournier, F., Diaz-Marin, R. et al. Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results. Nat Med 30, 443–454 (2024). https://doi.org/10.1038/s41591-024-02802-4

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