Chemokine CCL5 promotes robust optic nerve regeneration and mediates many of the effects of CNTF gene therapy
- 24 February 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 118 (9)
- https://doi.org/10.1073/pnas.2017282118
Abstract
Ciliary neurotrophic factor (CNTF) is a leading therapeutic candidate for several ocular diseases and induces optic nerve regeneration in animal models. Paradoxically, however, although CNTF gene therapy promotes extensive regeneration, recombinant CNTF (rCNTF) has little effect. Because intraocular viral vectors induce inflammation, and because CNTF is an immune modulator, we investigated whether CNTF gene therapy acts indirectly through other immune mediators. The beneficial effects of CNTF gene therapy remained unchanged after deleting CNTF receptor alpha (CNTFRα) in retinal ganglion cells (RGCs), the projection neurons of the retina, but were diminished by depleting neutrophils or by genetically suppressing monocyte infiltration. CNTF gene therapy increased expression of C-C motif chemokine ligand 5 (CCL5) in immune cells and retinal glia, and recombinant CCL5 induced extensive axon regeneration. Conversely, CRISPR-mediated knockdown of the cognate receptor (CCR5) in RGCs or treating wild-type mice with a CCR5 antagonist repressed the effects of CNTF gene therapy. Thus, CCL5 is a previously unrecognized, potent activator of optic nerve regeneration and mediates many of the effects of CNTF gene therapy. Significance CNTF is a leading therapeutic candidate for glaucoma and other ocular diseases and is widely used experimentally to promote axon regeneration after optic nerve injury. Paradoxically, whereas CNTF gene therapy is neuroprotective for retinal ganglion cells and promotes considerable regeneration following optic nerve injury, recombinant CNTF has little effect. We show that CNTF gene therapy exacerbates the inflammatory reaction to virally mediated gene therapy, leading to widespread expression of chemokine CCL5. Blocking CCL5 signaling abrogates most neuroprotective and axon-promoting effects of CNTF gene therapy, whereas recombinant CCL5 largely mimics the beneficial effects of CNTF gene therapy. Thus, this study identifies a potent, previously unknown agent for optic nerve regeneration and raises general questions about interpreting results of gene therapy studies.Keywords
Funding Information
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (LB)
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