Study finds retinal progenitor cell injections improve outcomes in rat model of diabetic retinopathy

The results of a new study support further investigation of intravitreal injection of retinal progenitor cells (RPCs) to treat diabetic retinopathy (DR) in a rat model of the disease,¹ investigators from the Gavin Herbert Eye Institute, Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, and the Neuroscience Research Institute, University of California, Santa Barbara, reported.

The procedure showed positive effects on the electroretinography (ERG) (b-wave, oscillatory potentials), optomotor response, and contrast sensitivity in actively treated eyes compared with controls, according to lead author Jing Yang, MD, PhD, from the University of California, Irvine. The investigators published their results in the International Journal of Molecular Sciences.

Yang and associates explained that DR impacts the blood vessels, specifically the retinal vasculature, and results in microvascular lesions, ischemia, and fluid or blood leakage in and around retinal tissue.² “Considerable research has gone into identifying the cellular and molecular basis of these changes. Most notably, the expression of vascular endothelial growth factor [VEGF] by ischemic tissue is known to be important to the pathophysiology of the disease,³ particularly in neovascular complications. Inhibiting this pathway has been an important strategy for the therapeutic management of DR,^2-5” they stated.

However, they pointed out what they described as an under-appreciated neural degenerative component in DR.^4,6,7 “While vascular abnormalities may wax and wane, the loss of retinal neurons results in permanent visual defects, often progressing to blindness. No current therapy directly addresses the irreversible component of neuronal cell death within the retina, although the process begins relatively early in the disease,²” they said.

In response to this gap in knowledge, they designed a study to determine if injection of RPCs could improve the anatomic and functional outcomes in a rat model of DR. “Crucially, no treatments address the loss of retinal neurons. Providing neuroprotection to the retina in DR can therefore be identified as an unmet medical need,⁴” the investigators said.

Using RPCs, they have developed a cell-based therapy that previously showed a “significant, reproducible neuroprotective benefit in rodent models of retinal degeneration^8-10” that is under evaluation in retinitis pigmentosa.^11-13 Their single-arm phase 1/2a trial of injection of allogeneic RPCs into the vitreous cavity, without surgery or immune suppression, has shown “excellent tolerability and provided initial indications of visual benefits,¹⁴” they reported. Given these results, they turned their attention to DR.

DR study of RPCs

Male Long Evans rats received streptozotocin (STZ) to induce diabetes, the development of which was confirmed before the intravitreal injection of rat and human RPCs 1 week post-induction.

The animals were tested at 6 weeks post-induction using ERG, optomotor response, and contrast sensitivity. The retinas were harvested at 8 weeks and analyzed.

Dr. Yang and associates reported, “The resulting data indicate that intravitreal RPCs are well tolerated in this model, were not rejected as allografts, and mediate a broad range of positive treatment effects on the STZ retina. These included improved vascular integrity, a relative normalization of VEGF expression, a preserved morphology of neuronal and non-neuronal retinal cell types, and enhanced electrophysiologic and behavioral measures of visual performance versus controls.”

They concluded, “We provide evidence that this cell-based treatment, RPCs, developed for use in inherited retinal diseases, may have applicability as a novel means of conferring cytoprotective effects in DR. These effects not only apply to neurons but to other impacted cell types within the retina as well. Of note, vascular integrity is greatly improved.”

References

1. Yang J, Lewis GP, Hsiang C-H, et al. Intravitreal transplantation of retinal progenitor cells improves outcome measures in a rat model of diabetic retinopathy. Int J Mol Sci. 2025;26:9450; https://doi.org/10.3390/ijms26199450

2. Diabetic Retinopathy. Available online: https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/diabetic-retinopathy (accessed on 20 August 2025).

3. Behl T, Kotwani A. Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy. Pharmacol Res. 2015;99:137–148.

4. Bianco L, Arrigo A, Aragona E, et al. Neuroinflammation and neurodegeneration in diabetic retinopathy. Front Aging Neurosci. 2022;14:937999.

5. Macaron MM, Al Sabbakh, N, Shami MZ, et al. Anti-VEGF Injections vs. Panretinal photocoagulation laser therapy for proliferative diabetic retinopathy: a systematic review and meta-analysis. Ophthalmol Retina. 2025;9:105–121.

6. Li Q, Zemel E, Miller B, Perlman I. Early retinal damage in experimental diabetes: Electroretinographical and morphological observations. Exp Eye Res. 2002;74:615–625.

7. Villarroel M, Ciudin A, Hernandez C, Simo R. Neurodegeneration: An early event of diabetic retinopathy. World J Diabetes. 2010;1:57–64.

8. Yang J, Lewis G, Hsiang C, et al. Amelioration of photoreceptor degeneration by intravitreal transplantation of retinal progenitor cells in rats. Int J Mol Sci. 2024;25:8060.

9. Cooper A, Cho J,Menges S, et al. Immunosuppressive treatment can alter visual performance in the RCS rat. J Ocul Pharmacol Ther. 2016;32:296–303.

10. Chen L, Yang J, Klassen H. Immune responses to sequential binocular transplantation of allogeneic retinal progenitor cells to the vitreous cavity in mice. Int J Mol Sci. 2023;24:6205.

11. Clinical Trial ID No. NCT02320812. Available online:https://clinicaltrials.gov/study/NCT02320812 (accessed on 20 August 2025).

12. Clinical Trial ID No. NCT03073733. Available online: https://clinicaltrials.gov/study/NCT03073733 (accessed on 20 August 2025).

13. Clinical Trial ID No. NCT06912633. Available online: https://clinicaltrials.gov/study/NCT06912633 (accessed on 20 August 2025).

14. Yang J, Kuppermann B, Liao D, et al. Retinal progenitor cells (jcell) for retinitis pigmentosa. Front Cell Neurosci. 2025;19:1646156.