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Ophthalmology https://doi.org/10.1038/s41591-024-02804-2

Rejuvenation of diabetic macular edema

Senolytic therapy for diabetic macular edema leading to disruption of the retinal neurovascular unit5. These stresses
result in endoplasmic reticulum stress, autophagy and the induction
(DME) refractory to anti-VEGF treatment of cell death pathways, such as apoptosis, pyroptosis and ferroptosis6.
appears safe, and preliminary data suggest a Cellular senescence, which is characterized by resistance to apoptosis —
as well as macromolecular damage, deregulated metabolism, mito-
therapeutic effect on visual acuity and macular chondrial dysfunction and production of a senescence-associated
thickness. secretory phenotype (SASP)7 — has recently been documented in dia-
betic retinopathy8. These processes have overlapping inciting stimuli
DME is the most common vision-threatening feature of diabetic reti- and cellular responses, notably nutrient deficiency and inflamma-
nal disease, affecting 4% of persons with diabetes1. Systemic therapy tion6. It is difficult to determine which disease mechanisms are active
involves controlling hyperglycemia and hypertension, while ocular in human eyes with diabetic retinopathy and therefore to identify
treatments include anti-vascular endothelial cell growth factor (VEGF) therapeutic targets. A recent study8 found elevated aqueous and
antibodies and corticosteroids (administered by intravitreal injection) vitreous humor cytokines and higher levels of extracellular DNA in
and occasionally macular laser. Real-world data reveal that anti-VEFG the vitreous of patients with proliferative retinopathy, suggesting
treatment leads to a mean improvement of only one line of visual acuity2, involvement of the cGAS–STING signaling pathway (a key mediator
and faricimab — a bispecific anti-VEGF and anti-angiopoietin-2 anti- of interferon-mediated inflammation and senescence). The authors
body — shows non-inferiority to anti-VEGF therapy3. Thus, new thera- also found increased STING expression in the nerve fiber layer and
pies are needed to sustain the viability of retinal neurons and prevent endothelial cells of diabetic mice, and deleting STING reduced expres-
loss of vision. In this issue of Nature Medicine, Crespo-Garcia et al.4 sion of the senescence markers.
provide a mechanistic rationale for targeting cellular senescence in Building on existing mechanistic evidence, Crespo-Garcia et al.4
diabetic retinopathy and evaluate intravitreal injection of a senolytic analyzed human donor retinas and vitreous, insulin-deficient mice, and
drug (UBX1325, which inhibits the anti-apoptotic protein BCL-xL) in a human retinal endothelial cells to establish biochemical, functional
phase 1 study. Their results suggest a beneficial and long-acting effect and pathological evidence of senescence in the pathophysiology of
of UBX1325 on visual acuity and macular thickness in patients with DME DME. They confirmed previous findings of elevated cytokine levels
refractory to anti-VEGF treatment. in the vitreous of patients with diabetes. Single-cell RNA sequencing
Diabetes inflicts multiple metabolic stresses on the retina — includ- data from diabetic mice indicated that the most perturbed cell popula-
ing hyperglycemia and altered concentrations of circulating and tissue tions were cone photoreceptors, Müller cell glia and endothelial cells.
amino acids and lipids — as well as secondary neuroinflammation, Intravitreal injection of UBX1325 reduced caspase activity in mice with

Lipid and amino acid Glucose Antihyperglycemic

Autophagy
Apoptosis
Senolytics
Senescent cell Anti-VEGF
Nutrient deficiency

Necrosis
Ferroptosis VEGF

Pyroptosis
Multivalent
Steroid Inflammation Ang-2 neutralization

Endothelial cells responding to stress in DR SASP factors Stressor Therapeutic strategy

Fig. 1 | Senolytic therapy as a new option for diabetic macular edema. permeability in neighboring cells, mediated by the SASP. Senolytic therapy
Among multiple mechanisms, senescent cells lose intercellular junctions rejuvenates the blood–retinal barrier, while other therapies target various
and concomitantly increase paracellular flux and further promote vascular cellular stressors. DR, diabetic retinopathy; ER, endoplasmic reticulum.

nature medicine Volume 30 | February 2024 | 346–347 | 346

oxygen-induced retinopathy and reduced retinal vascular permeability targets and compounds is in progress10, which may benefit patients
in diabetic mice. In a phase 1 study of 8 participants with DME that was with diabetic retinal disease.
non-responsive to anti-VEGF therapy, retinal function (as measured by In the meantime, the results of this initial clinical trial from
electroretinography and visual acuity over 24 weeks) improved in two Crespo-Garcia et al.4 raise new questions and will stimulate additional
dose cohorts after a single intravitreal injection; macular thicknesses research to address them. For example, what stresses increase BCL-xL
also declined throughout the observation period (Fig. 1). No serious content in the retina? In the course of DME, what is the sequence by
ocular or systemic adverse events related to UBX1325 were noted. which senescence becomes a dominant response, and which other
These encouraging results are typical of small phase 1 studies and stress responses are active simultaneously with senescence? Are
should be interpreted with caution. Although no safety issues were endothelial cells the primary site of the senescence response or its
reported with UBX1325, this was a short-term study and the safety of this target? What is the topographic distribution of senescence across the
agent warrants further evaluation. Senolytics have mainly been used retina over the course of disease severity? Does loss of senescent cells
for systemic diseases and so their effects on vision (and the potential reduce chronic neuroinflammation in diabetic retinas? These ques-
for ocular toxicity) are largely unknown. A retrospective cohort study tions might be addressed by quantitative vitreous or aqueous fluid
revealed no exacerbation of glaucoma in patients who received seno- analyses, or potential non-invasive determination of retinal senescence
lytic therapy for systemic diseases9, but the sample size was again small. or apoptosis, similar to in vivo detection of apoptotic retinal cells with
The mode of action of UBX1325 is to remove senescent cells and intravenous injection of fluorescently labelled annexin A5 (ref. 11).
repair retinal vasculature. Prior therapeutic strategies involved inhi- It is likely that multiple mechanisms of cell stress and death are
bition of cell death to leave both healthy and damaged cells alive. active in diabetic retinopathy and it will be important to treat their
However, recent advances have shown that some dying cells release relative contributions to achieve optimal results. Senolytic therapy is
damage-associated molecular patterns and cytotoxic factors, eliciting a promising emerging strategy; rejuvenation by stem cell transplanta-
immunogenic cell death and the propagation of degeneration, respec- tion is another. For now, the study from Crespo-Garcia et al.4 marks the
tively. Thus, it is necessary to determine the appropriate regulation of beginning of a new era of retinal rejuvenation for the neurovascular
cell death without damaging neighboring cells and tissues. By selec- consequences of diabetes.
tively clearing senescent cells, senolytic drugs may reduce the focal
secretion associated with the SASP and the disruption of intercellular Tomoaki Murakami1 & Thomas W. Gardner2
tight junctions in endothelial cells4. Department of Ophthalmology and Visual Sciences, Kyoto University
1

UBX1325 may be the first senolytic to be evaluated for diabetic Graduate School of Medicine, Kyoto, Japan. 2Department of
retinopathy, but it will not be the last. Several lines of senolytic drugs Ophthalmology and Visual Sciences, Kellogg Eye Center, University of
have been shown to modulate mitochondrial dysfunction and patho- Michigan, Ann Arbor, MI, USA.
logical phosphorylation signals — which are potential targets for treat- e-mail: mutomo@kuhp.kyoto-u.ac.jp; tomwgard@umich.edu
ment of diabetic complications. In mitochondria, BCL-xL and BCL-2
counteract the increased mitochondrial outer membrane permeability Published online: 8 February 2024
that is induced by BAX and BAK, and inhibitors of BCL-xL and BCL-2 act
as senolytics. UBX1325 is a BCL-xL inhibitor, but other promising mito- References
chondrial targets (and related senolytic drugs) are yet to be assessed 1. Teo, Z. L. et al. Ophthalmology 128, 1580–1591 (2021).
2. Ciulla, T. A., Pollack, J. S. & Williams, D. F. Br. J. Ophthalmol. 105, 216–221 (2021).
for treatment of vascular and neural alterations in diabetic retinopathy. 3. Wykoff, C. C. et al. Lancet 399, 741–755 (2022).
Phosphorylation signals are also targets of interest; SRC and phospho- 4. Crespo-Garcia, S. et al. Nat. Med. https://doi.org/10.1038/s41591-024-02802-4 (2024).
5. Antonetti, D. A., Silva, P. S. & Stitt, A. W. Nat. Rev. Endocrinol. 17, 195–206 (2021).
inositide 3-kinase are inducers of vascular permeability and survival
6. Oshitari, T. Int. J. Mol. Sci. 24, 12919 (2023).
signals, respectively, in vascular endothelial cells, and are targets of 7. Gorgoulis, V. et al. Cell 179, 813–827 (2019).
the senolytic drugs dasatinib and fisetin. Senomorphic drugs (for 8. Liu, H. et al. JCI Insight 8, e168945 (2023).
9. El-Nimri, N. W. et al. Sci. Rep. 10, 21752 (2020).
example, metformin), which modulate rather than remove senescent
10. Wong, F., Omori, S., Donghia, N. M., Zheng, E. J. & Collins, J. J. Nat. Aging 3,
cells, suppress SASP secretion and may slow age-related degeneration. 734–750 (2023).
Artificial intelligence-based exploration of novel senescence-related 11. Cordeiro, M. F. et al. Prog. Retin. Eye Res. 86, 100976 (2022).

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