title: Pigment epithelium-derived factor gene therapy targeting retinal ganglion cell injuries: neuroprotection against loss of function in two animal models.
abstract: Lentiviral vectors are promising tools for the treatment of chronic retinal diseases including glaucoma, as they enable stable transgene expression. We examined whether simian immunodeficiency virus (SIV)-based lentiviral vector-mediated retinal gene transfer of human pigment epithelium-derived factor (hPEDF) can rescue rat retinal ganglion cell injury. Gene transfer was achieved through subretinal injection of an SIV vector expressing human PEDF (SIV-hPEDF) into the eyes of 4-week-old Wistar rats. Two weeks after gene transfer, retinal ganglion cells were damaged by transient ocular hypertension stress (110 mmHg, 60 min) and N-methyl-d-aspartic acid (NMDA) intravitreal injection. One week after damage, retrograde labeling with 4',6-diamidino-2-phenylindole (DAPI) was done to count the retinal ganglion cells that survived, and eyes were enucleated and processed for morphometric analysis. Electroretinographic (ERG) assessment was also done. The density of DAPI-positive retinal ganglion cells in retinal flat-mounts was significantly higher in SIV-hPEDF-treated rats compared with control groups, in both transient ocular hypertension and NMDA-induced models. Pattern ERG examination demonstrated higher amplitude in SIV-hPEDF-treated rats, indicating the functional rescue of retinal ganglion cells. These findings show that neuroprotective gene therapy using hPEDF can protect against retinal ganglion cell death, and support the potential feasibility of neuroprotective therapy for intractable glaucoma.
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yonemitsu
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Goto
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Murakami
authors.forename: Noriko
authors.initials: N
authors.lastname: Yoshida
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tabata
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Shozo
authors.initials: S
authors.lastname: Tobimatsu
authors.forename: Katsuo
authors.initials: K
authors.lastname: Sueishi
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishibashi
mesh_terms: D000818:Animals; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D005131:Eye Injuries / Q000139:chemically induced / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D005136:Eye Proteins / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling; D007211:Indoles; D016202:N-Methylaspartate / Q000009:adverse effects; D009414:Nerve Growth Factors / Q000235:genetics*; D009798:Ocular Hypertension / Q000150:complications; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000293:injuries*; D012165:Retinal Ganglion Cells / Q000473:pathology*; D015843:Serpins / Q000235:genetics*; D015302:Simian Immunodeficiency Virus; D018709:Statistics, Nonparametric; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D007211:Indoles; D016202:N-Methylaspartate; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C007293:DAPI