Inhibition of Sema-3A Promotes Cell Migration, Axonal Growth, and Retinal Ganglion Cell Survival

Semaphorin 3A (Sema-3A) is a secreted protein that deflects axons from inappropriate regions and induces neuronal cell death. Intravitreal application of polyclonal antibodies against Sema-3A prevents loss of retinal ganglion cells ensuing from axotomy of optic nerves. This suggested a therapeutic a...

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Published in:Translational vision science & technology 2021-11, Vol.10 (10), p.16-16
Main Authors: Nitzan, Anat, Corredor-Sanchez, Miriam, Galron, Ronit, Nahary, Limor, Safrin, Mary, Bruzel, Marina, Moure, Alejandra, Bonet, Roman, Pérez, Yolanda, Bujons, Jordi, Vallejo-Yague, Enriqueta, Sacks, Hagit, Burnet, Michael, Alfonso, Ignacio, Messeguer, Angel, Benhar, Itai, Barzilai, Ari, Solomon, Arieh S
Format: Article
Language:English
Subjects:
Animals
Axons
Axotomy
Cell Movement
Humans
Retinal Ganglion Cells
Semaphorin-3A
Special Issue
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Summary:Semaphorin 3A (Sema-3A) is a secreted protein that deflects axons from inappropriate regions and induces neuronal cell death. Intravitreal application of polyclonal antibodies against Sema-3A prevents loss of retinal ganglion cells ensuing from axotomy of optic nerves. This suggested a therapeutic approach for neuroprotection via inhibition of the Sema-3A pathway. To develop potent and specific Sema-3A antagonists, we isolated monoclonal anti-Sema-3A antibodies from a human antibody phage display library and optimized low-molecular weight Sema-3A signaling inhibitors. The best inhibitors were identified using in vitro scratch assays and semiquantitative repulsion assays. A therapeutic approach for neuroprotection must have a long duration of action. Therefore, antibodies and low-molecular weight inhibitors were formulated in extruded implants to allow controlled and prolonged release. Following release from the implants, Sema-3A inhibitors antagonized Sema-3A effects in scratch and repulsion assays and protected retinal ganglion cells in animal models of optic nerve injury, retinal ischemia, and glaucoma. Collectively, our findings indicate that the identified Sema-3A inhibitors should be further evaluated as therapeutic candidates for the treatment of Sema-3A-driven central nervous system degenerative processes.
ISSN:2164-2591
2164-2591
DOI:10.1167/tvst.10.10.16