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bioRxiv · 10.1101/2024.03.07.583961

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

Soucy, J. R.·Kriukov, E.·Oswald, J.·Masland, J.·Pernstich, C.·Baranov, P.
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Abstract

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. Table of Contents Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/583961v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@62d2eorg.highwire.dtl.DTLVardef@1805635org.highwire.dtl.DTLVardef@9bbea7org.highwire.dtl.DTLVardef@101e2f9_HPS_FORMAT_FIGEXP M_FIG C_FIG Engineering the retinal environment with neurotrophic factors to mimic development improves donor and host neuron survival, outgrowth, and function in an optic neuropathy mouse model.

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Soucy, J. R., Kriukov, E., Oswald, J., Masland, J., Pernstich, C., Baranov, P.. 2024-03-12. Sustained neurotrophic factor cotreatment enhances donor and host retinal ganglion cell survival in mice. https://doi.org/10.1101/2024.03.07.583961

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