Müller Glia-Derived Small Extracellular Vesicles as Potential Therapy of Early-Stage Diabetic Retinopathy

Abstract

Purpose : Müller glia (MG) is the primary glial cell unique in the retina and is a major source of neuroprotective and vascular permeability factors. We aim to investigate the therapeutic potential of intraocular MG derived small extracellular vesicle (MG-sEV) treatment to modulate microenvironment in diabetic retinopathy (DR).

Methods : sEV were recovered from the conditioned culture media of primary mouse MG cells followed by comprehensive characterization established in our lab. Diabetes mellitus (DM) was induced in male mice using streptozotocin (STZ) to provoke DR (STZ-DR). Ten weeks (early-stage DR) following DM induction, mice received 2 biweekly intravitreal (IVT) injections of MG-sEV. Optical coherence tomography (OCT) 2 weeks after each MG-sEV treatment was obtained to evaluate changes in retinal thickness, with a detailed analysis performed using ImageJ of the inner (NFL to IPL), middle (INL to ONL), and outer (IS/OS to RPE) retinal layers.

Results : Similar to previous studies, we confirmed a 5% reduction in total retinal thickness in the early-stage of STZ-DR compared to wildtype mice (p < 0.002), with no observed vascular leakage or neovascularization (NV) development. During the course of early-stage STZ-DR, the retinal thinning continued to progress. In contrast, the MG-sEV treated eyes showed retinal thickness preservation; 8% (p < 0.002), 12% (p < 0.00001), and 7% (p < 0.001) preservation in inner, outer, and total retinal layer thicknesses, respectively, compared to untreated eyes (Figure, n=10).

Conclusions : sEV mediated MG secretome may have the potential to mitigate early-stage DR. While these initial results are encouraging, additional studies in vascular leakage, inflammation, and glial activation are underway.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

A) OCT-based image analysis performed two weeks after the course of two MG-sEV intravitreal injections showed a 7% (p < 0.001) preservation in total retinal thickness of the treated eyes compared to untreated eyes. B) Breakdown analysis of specific retinal layers showed a 8% (p < 0.002) and 12% (p < 0.00001) preservation in the inner and outer retinal thickness of the treated eyes compared to untreated eyes, respectively. Comparison of the middle layers of the two groups did not reveal any statistically significant difference. Inner: NFL to IPL, middle: INL to ONL, outer: IS/OS to RPE. ** p < 0.01, *** p < 0.001.