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Idelalisib inhibits experimental proliferative vitroretinopathy

Abstract

Proliferative vitreoretinopathy (PVR) is a fibrotic eye disease that develops after rhegmatogenous retinal detachment surgery and open-globe traumatic injury. Idelalisib is a specific inhibitor of phosphoinositide 3-kinase (PI3K) δ. While PI3Kδ is primarily expressed in leukocytes, its expression is also considerably high in retinal pigment epithelial (RPE) cells, which play a crucial part in the PVR pathogenesis. Herein we show that GeoMx Digital Spatial Profiling uncovered strong expression of fibronectin in RPE cells within epiretinal membranes from patients with PVR, and that idelalisib (10 μM) inhibited Akt activation, fibronectin expression and collagen gel contraction induced by transforming growth factor (TGF)-β2 in human RPE cells. Furthermore, we discovered that idelalisib at a vitreal concentration of 10 μM, a non-toxic dose to the retina, prevented experimental PVR induced by intravitreally injected RPE cells in rabbits assessed by experienced ophthalmologists using an indirect ophthalmoscope plus a + 30 D fundus lens, electroretinography, optical coherence tomography and histological analysis. These data suggested idelalisib could be harnessed for preventing patients from PVR.

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Fig. 1: GeoMx Digital Spatial Profiling of ERMs from patients with PVR.
Fig. 2: Idelalisib inhibited Akt activation induced by TGF-β2 in human RPE cells.
Fig. 3: Idelalisib blocked TGF-β2 induced collagen gel contraction.
Fig. 4: Examination of idelalisib toxicity in rabbit eyes.
Fig. 5: Idelalisib prevented experimental PVR in rabbits.

Data availability

The materials described in this report, including all relevant raw data, will be freely available to any researcher wishing to use them for noncommercial purposes, without breaching participant confidentiality.

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Funding

This work was supported by the National Natural Science Foundation of China (82070989) to H.L., China Scholarship Council (201806320148) to H.H., the National Natural Science Foundation of China (81860172) to XH and the Sanming Project of Medicine in Shenzhen (SZSM202011015) to G.Z., S.Z .and H.L. No funding bodies had any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Contributions

D.L., H.H. and X.H. performed most of the experiments, analyzed the results, and made equal contributions to this work; D.F., H.Q,. Z.H., L.W. and G.M. performed some of the experiments; G.Z., J.T. and B.V. revised the manuscript; SZ and HL conceived the experiments, analyzed the data and wrote the manuscript.

Corresponding authors

Correspondence to Shaochong Zhang or Hetian Lei.

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Competing interests

B.V. is a consultant for Karus Therapeutics (Oxford, UK), iOnctura (Geneva, Switzerland) and Venthera (Palo Alto, CA, USA) and has received speaker fees from Gilead Sciences (Foster City, US), and all other authors in this article declare that they have no conflicts of interest with the contents of this article.

Ethics Approval/Consent to Participate

Ethical approvals for harvesting ERMs from patients with PVR at Shenzhen Eye Hospital and for collecting control breast epithelial tissues from patients with breast cancers at Zhejiang Cancer Hospital were obtained from the Ethical Committees of Shenzhen Eye Hospital, Shenzhen, China and at Zhejiang Tumor Hospital, Hangzhou, China, respectively. Patients with PVR or cancer were consent to participate in these research programs, which adhered to the tenets of the Declaration of Hlesinki.

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Dong, L., Han, H., Huang, X. et al. Idelalisib inhibits experimental proliferative vitroretinopathy. Lab Invest (2022). https://doi.org/10.1038/s41374-022-00822-7

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