Pigment epithelium-derived factor gene therapy targeting retinal ganglion cell injuries: Neuroprotection against loss of function in two animal models

Masanori Miyazaki, Yasuhiro Ikeda, Yoshikazu Yonemitsu, Yoshinobu Goto, Yusuke Murakami, Noriko Yoshida, Toshiaki Tabata, Mamoru Hasegawa, Shozo Tobimatsu, Katsuo Sueishi, Tatsuro Ishibashi

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25 Citations (Scopus)

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 (110mmHg, 60min) 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.

Original languageEnglish
Pages (from-to)559-565
Number of pages7
JournalHuman Gene Therapy
Volume22
Issue number5
DOIs
Publication statusPublished - May 1 2011

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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