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April 1st, 2025
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Schepens Eye Research Institute of Mass. Eye & Ear
bioengineering
biorxiv

Sustained neurotrophic factor cotreatment enhances donor and host retinal ganglion cell survival in mice

Soucy, J. R.Open in Google Scholar•Oswald, J.Open in Google Scholar•Kriukov, E.Open in Google Scholar•Phay, M.Open in Google Scholar•Masland, J.Open in Google Scholar•Pernstich, C.Open in Google Scholar•Baranov, P.Open in Google Scholar

Retinal ganglion cells (RGCs) lack regenerative capacity in mammals, and their degeneration in glaucoma leads to irreversible blindness. Autologous and allogeneic RGC replacement with stem cell-derived neurons has been established as a promising strategy for vision restoration, but it has been limited by relatively low (<1%) survival rates of donor cells in the hostile microenvironment of a diseased retina and optic nerve. Brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) are known to support the survival of neurons, including RGCs in. vitro and in vivo. Here, we aim to improve donor RGC survival by supplementing our in vitro cultures and in transplants with a slow-release formulation of these neuroprotective agents. We show that slow-release BDNF/GDNF significantly enhances RGC differentiation, survival, and function in vitro. Furthermore, we demonstrated that BDNF/GDNF co-treatment improved mouse and human stem cell-derived donor RGC transplantation outcomes by 2.7- and 15-fold in mice, respectively. Lastly, we show that slow-release BDNF/GDNF provides neuroprotective effects on host RGCs, preserving retinal function in a model of optic neuropathy. Altogether, this approach of engineering the retinal microenvironment with slow-release neurotrophic factors significantly enhances both donor and host neuron survival, representing a promising approach for treating glaucoma and other optic neuropathies.

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