title: Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma.
abstract: Glaucoma is a multifactorial disease resulting in the death of retinal ganglion cells (RGCs) and irreversible blindness. Glaucoma-associated RGC death depends on the proapoptotic and proinflammatory activity of membrane-bound Fas ligand (mFasL). In contrast to mFasL, the natural cleavage product, soluble Fas ligand (sFasL) inhibits mFasL-mediated apoptosis and inflammation and, therefore, is an mFasL antagonist. DBA/2J mice spontaneously develop glaucoma and, predictably, RGC destruction is exacerbated by expression of a mutated membrane-only FasL gene that lacks the extracellular cleavage site. Remarkably, one-time intraocular adeno-associated virus-mediated gene delivery of sFasL provides complete and sustained neuroprotection in the chronic DBA/2J and acute microbead-induced models of glaucoma, even in the presence of elevated intraocular pressure. This protection correlated with inhibition of glial activation, reduced production of TNF-α, and decreased apoptosis of RGCs and loss of axons. These data indicate that cleavage of FasL under homeostatic conditions, and the ensuing release of sFasL, normally limits the neurodestructive activity of FasL. The data further support the notion that sFasL, and not mFasL, contributes to the immune-privileged status of the eye.
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114.
authors.forename: Anitha
authors.identifier: 0000-0001-9581-7125
authors.initials: A
authors.lastname: Krishnan
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114.|Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, People's Republic of China; and.
authors.forename: Fei
authors.initials: F
authors.lastname: Fei
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jones
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655.
authors.forename: Patricia
authors.identifier: 0000-0003-4531-0494
authors.initials: P
authors.lastname: Busto
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655.
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Ksander
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114; meredith_gregory@meei.harvard.edu.
authors.forename: Meredith
authors.initials: M
authors.lastname: Gregory-Ksander
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002908:Chronic Disease; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015316:Genetic Therapy; D005901:Glaucoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D000066829:Neuroprotection; D012165:Retinal Ganglion Cells / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D014409:Tumor Necrosis Factor-alpha