UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy

Abstract

Purpose : Retinal vasculopathies account for the primary causes of loss of sight in the industrialized world and current standards present significant side effects. To develop novel treatment paradigms, we developed UBX1325, a novel small molecule inhibitor of specific subtypes within the B-cell lymphoma 2 (Bcl-2) family of apoptosis regulatory proteins and assessed its efficacy in senescence-associated models of retinopathy.

Methods : Target engagement (TE), decreased Bcl-xL:Bim or Bcl-2:Bim complexes, was measured by an electrochemiluminescence-based assay in retinal lysates from C57BL/6 mice after intravitreal (IVT) injection of UBX1325. Initiation of apoptosis (mechanism engagement, ME) was measured by caspase-3/7 activation. Adult mice and neonatal mice from oxygen induced retinopathy (OIR; 75% O₂ from post-natal day (P)7-P12) or normoxic controls were used for TE and ME measurements. Vascular endpoints (neovascular and avascular area) were evaluated at P17 by isolectin B4 staining in OIR mice given a single IVT injection of UBX1325 at P12. UBX1325 was also studied in the streptozotocin (STZ)-induced retinopathy model. UBX1325 was injected IVT at weeks 8 and 9 post-STZ, and retinal endpoints were measured at week 10. Vascular leakage was evaluated by Evans blue dye extravasation into the retina after intravenous injection. The dark-adapted electroretinogram was used to assess retinal function with increasing flash intensity. Retinal gene expression was evaluated for a limited panel of targets by qRT-PCR.

Results : IVT administration of UBX1325 lead to a reduction of anti-apoptotic Bcl-xL:Bim complexes in the mouse retina. Bcl-xL TE (37-81%) in OIR animals resulted in caspase-3/7 activation (3-9-fold) and improvements in both retinal neovascularization (58-71%) and avascular area (32-52%). In the diabetic mouse, UBX1325 injection resulted in reduced retinal vascular permeability (78-90%) and an improved ERG (a- and b-wave amplitude).

Conclusions : Inhibition of retinal Bcl-xL by UBX1325 promotes apoptosis in the senescence-associated OIR model. UBX1325 improves retinal vasculature in both the OIR and STZ mice, and demonstrates differentiation over anti-VEGF agents in OIR. Collectively, our data support development of UBX1325 for retinal vasculopathies and initial clinical evaluation of UBX1325 in patients with diabetic macular edema (DME).

This is a 2021 ARVO Annual Meeting abstract.