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Published on: July 16, 2019
Inhibition of Sema-3A Promotes Cell Migration, Axonal Growth, and Retinal Ganglion Cell Survival
Anat Nitzan1, Miriam Corredor-Sanchez2, Ronit Galron1
1Department of Neurobiology, George S. Wise, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Purpose:
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.
Methods:
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.
Results:
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.
Conclusions And Translational Relevance:
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.
