A recent study published in the journal Nature’s medicine showed that targeting senescent cells in the retina could be a long-lasting disease-modifying treatment for diabetic macular edema (DME).
The retina is vascularized to support the high energy demands for vision. As such, the neural retina and its associated blood vessels are susceptible to metabolic disturbances, such as in diabetic retinopathy (DR). Breakdown of the blood-retinal barrier at various stages of DR leads to DME, in which extravasation of plasma and proteins into the intra- and sub-retinal space results in swelling and visual loss.
Current standard care for DME involves anti-vascular endothelial growth factor (VEGF) agents, which reduce macular edema and improve visual acuity. However, the therapeutic response remains suboptimal in most patients, with efficacy decreasing over time. Also, while corticosteroids can effectively reduce edema, they can increase intraocular pressure. Exploring alternative safe, long-lasting, disease-modifying DME treatments may benefit patients.
Study: Therapeutic targeting of cellular senescence in diabetic macular edema: results of preclinical and phase 1 trials.. Image credit: Anukool Manoton/Shutterstock
Research and results
In the current study, the researchers investigated how senescent cells contribute to DME. First, they estimated the levels of prototypical senescence-associated secretory phenotype (SASP) factors in the vitreous of DME patients. It revealed increased interleukin (IL)-6, IL-8, and plasminogen activator inhibitor 1 (PAI1) levels in DME patients compared to non-vascular pathology controls.
Further, the expression of p16INK4A, a cell cycle regulator associated with senescence, in postmortem retinal sagittal sections of DME patients compared to age- and sex-matched non-diabetic control retinas. Extended p16INK4A Expression was observed in the inner retina, choroidal layer, and Bruch’s membrane in retinas with DME. p16INK4A Expression was restricted to regions of suspected disease activity.
Next, the researchers examined retinal bulk RNA sequencing (RNA-seq) datasets from mice and rats with streptozotocin (STZ)-induced diabetes. Genes for cellular senescence and SASP were positively correlated in STZ-treated animals compared to controls. For increased resolution, they evaluated single-cell RNA-seq (scRNA-seq) datasets from mice with STZ-induced diabetes.
Cone photoreceptors, endothelial cells (ECs), and Müller glia were the most transcriptionally perturbed populations compared to non-diabetic controls. Sub-clustering of ECs revealed three distinct sub-clusters (EC1 – EC3). EC2 was predominant in the diabetic retina and enriched for genes associated with vascular complications in diabetes and genes involved in the regulation of cellular senescence in ECs and other cell types.
Further experiments suggested that retinal senescent ECs impair barrier function. Next, it was assessed whether hyperglycemia could trigger senescent phenotypes in DME. Human retinal microvascular ECs (HRMECs) were exposed to a medium with high D-glucose (Hg) or the isomotic control enantiomer (CTR). Five weeks after HG exposure, global cell proliferation was reduced by 25% and cells with senescence-associated markers increased threefold compared to CTR.
Anti-apoptotic proteins such as B-cell lymphoma 2 (BCL2) and BCL-xL were induced in Hg-treated HRMECs. Further, the researchers tested whether targeting BCL-xL could improve barrier function in the diabetic retina. A small-molecule inhibitor, UBX1967, was administered intravenously to diabetic rats eight and nine weeks after STZ treatment. It significantly reduced protein levels of BCL-xL and PAI1 at 10 weeks of diabetes.
Retinal BCL2 levels were unchanged, while transcript levels of inflammatory SASP factors were significantly decreased. Notably, UBX1967 treatment reduced retinal vascular permeability by 40% to 50%. In addition, whole-field scotopic electroretinography showed that UBX1967 treatment improved retinal function. The researchers developed UBX1325, a phosphate pro-drug with senolytic properties, as a therapeutic candidate.
Confirmed BCL-xL target engagement for UBX0601 (the active molecule of UBX1325) in senescent HRMECs. The researchers noted that senescent cells must be present for apoptosis to be initiated by BCL-xL inhibition. Apoptosis with Bcl-xl inhibition did not occur in the healthy retina. UBX1325 also reduced retinal vascular permeability (40% – 50%) in the STZ model compared to vehicle-treated controls.
Next, the team conducted a phase 1 safety and tolerability trial of UBX1325 in patients with advanced DME or neovascular age-related macular degeneration for whom anti-VEGF therapy was no longer beneficial. Intravitreal UBX1325 injection was well tolerated with no reports of inflammation. However, some treatment-emergent adverse events (TEAEs) were observed that were considered unrelated to UBX1325.
TEAEs were observed in patients receiving higher doses, which were considered to be due to their underlying disease. Preliminary safety evaluations suggested that UBX1325 could be advanced into later-stage clinical studies. Plasma levels of UBX1325 and UBX0601 were below the lower limit of quantification. In DME patients, a single injection improves visual acuity. Higher UBX1325 dose and decreased central subfield thickness.
Together, the results illustrate that therapeutic clearance of senescent cells may result in long-term improvement in visual function in DME patients. Intravitreal administration of a Bcl-XL inhibitor eliminated senescent ECs, thereby reducing local inflammation and improving barrier function, ultimately increasing visual function. Efficacy data suggested that vision improvement persisted for at least six months.
- Crespo-Garcia S, Fournier F, Diaz-Marin R, et al. Therapeutic targeting of cellular senescence in diabetic macular edema: results of preclinical and phase 1 trials. Nat Med2024, DOI: 10.1038/s41591-024-02802-4, https://www.nature.com/articles/s41591-024-02802-4