title: Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma.
abstract: The endothelin system is implicated in various human and animal glaucomas. Targeting the endothelin system has great promise as a treatment for human glaucoma, but the cell types involved and the exact mechanisms of action are not clearly elucidated. Here, we report a detailed characterization of the endothelin system in specific cell types of the optic nerve head (ONH) during glaucoma in DBA/2J mice. First, we show that key components of the endothelin system are expressed in multiple cell types. We discover that endothelin 2 (EDN2) is expressed in astrocytes as well as microglia/monocytes in the ONH. The endothelin receptor type A (Ednra) is expressed in vascular endothelial cells, while the endothelin receptor type B (Ednrb) receptor is expressed in ONH astrocytes. Second, we show that Macitentan treatment protects from glaucoma. Macitentan is a novel, orally administered, dual endothelin receptor antagonist with greater affinity, efficacy and safety than previous antagonists. Finally, we test the combinatorial effect of targeting both the endothelin and complement systems as a treatment for glaucoma. Similar to endothelin, the complement system is implicated in a variety of human and animal glaucomas, and has great promise as a treatment target. We discovered that combined targeting of the endothelin (Bosentan) and complement (C1qa mutation) systems is profoundly protective. Remarkably, 80% of DBA/2J eyes subjected to this combined inhibition developed no detectable glaucoma. This opens an exciting new avenue for neuroprotection in glaucoma.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA. Electronic address: gareth.howell@jax.org.
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Howell
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA.
authors.forename: Katharine H
authors.initials: KH
authors.lastname: MacNicoll
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Braine
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA.
authors.forename: Ileana
authors.initials: I
authors.lastname: Soto
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA.
authors.forename: Danilo G
authors.initials: DG
authors.lastname: Macalinao
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Sousa
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA; The Howard Hughes Medical Institute, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA; Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA. Electronic address: simon.john@jax.org.
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D000077300:Bosentan; D015922:Complement C1q / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists / Q000627:therapeutic use; D019333:Endothelin-2 / Q000378:metabolism*; D005901:Glaucoma / Q000150:complications* / Q000473:pathology; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D009410:Nerve Degeneration / Q000209:etiology* / Q000473:pathology / Q000628:therapy*; D011743:Pyrimidines / Q000627:therapeutic use; D044022:Receptor, Endothelin A / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D065130:Endothelin A Receptor Antagonists; D019333:Endothelin-2; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D015922:Complement C1q; D000077300:Bosentan; C533860:macitentan
keywords: Complement; DBA/2J; Endothelin; Glaucoma; Optic nerve head