June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy
Author Affiliations & Notes
  • Pamela Tsuruda
    UNITY Biotechnology, South San Francisco, California, United States
  • Shawnta Chaney
    UNITY Biotechnology, South San Francisco, California, United States
  • Agnieszka Dejda
    Hopital Maisonneuve-Rosemont Centre de Recherche, Montreal, Quebec, Canada
  • Sonali Dasgupta
    UNITY Biotechnology, South San Francisco, California, United States
  • Sergio Crespo-Garcia
    Hopital Maisonneuve-Rosemont Centre de Recherche, Montreal, Quebec, Canada
  • Surabhi Rao
    UNITY Biotechnology, South San Francisco, California, United States
  • Scott Armstrong
    UNITY Biotechnology, South San Francisco, California, United States
  • Dan Marquess
    UNITY Biotechnology, South San Francisco, California, United States
  • Przemyslaw Sapieha
    Hopital Maisonneuve-Rosemont Centre de Recherche, Montreal, Quebec, Canada
  • Pedro Beltran
    UNITY Biotechnology, South San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Pamela Tsuruda, UNITY Biotechnology (E); Shawnta Chaney, UNITY Biotechnology (E); Agnieszka Dejda, UNITY Biotechnology (F); Sonali Dasgupta, UNITY Biotechnology (E); Sergio Crespo-Garcia, UNITY Biotechnology (F); Surabhi Rao, UNITY Biotechnology (E); Scott Armstrong, UNITY Biotechnology (E); Dan Marquess, UNITY Biotechnology (E); Przemyslaw Sapieha, UNITY Biotechnology (C); Pedro Beltran, UNITY Biotechnology (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1163. doi:
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      Pamela Tsuruda, Shawnta Chaney, Agnieszka Dejda, Sonali Dasgupta, Sergio Crespo-Garcia, Surabhi Rao, Scott Armstrong, Dan Marquess, Przemyslaw Sapieha, Pedro Beltran; UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1163.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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