Synergistic neuroprotective effect via simian lentiviral vector-mediated simultaneous gene transfer of human pigment epithelium-derived factor and human fibroblast growth factor-2 in rodent models of retinitis pigmentosa.
BACKGROUND
We previously demonstrated that a new lentiviral vector derived from nonpathogenic simian immunodeficiency virus (SIVagm) was efficient and safe for long-lasting retinal gene transfer, and that it provided the significant therapeutic effect of expressing human pigment epithelium-derived factor (hPEDF) in Royal College of Surgeons (RCS) rats. In the present study, to obtain a more pronounced outcome, we assessed the potential synergistic effect of the simultaneous gene transfer of hPEDF and human fibroblast growth factor-2 (hFGF-2) by improved third-generation SIV on RCS rats and retinal degeneration slow (rds) mice, because the former targets the primary neurons, including photoreceptor cells (PCs), whereas the latter is effective for targeting secondary neural cells, including Muller cells.


METHODS
Vector solution (SIV-hPEDF, SIV-hFGF-2, a 1 : 1 mixture of SIV-hPEDF and SIV-hFGF-2, or SIV-enhanced green fluorescent protein) was injected into the peripheral subretinal space of 3-week-old RCS rats or rds mice. Histopathological and electroretinographic assessments were made at several points after gene transfer.


RESULTS
Administration of SIV-hPEDF or SIV-hFGF-2 significantly delayed the histological PC degeneration and electrical deficit in RCS rats, and these delays were synergistically and significantly pronounced by SIV-hPEDF + SIV-hFGF-2 (1 : 1 mixture). In rds mice, functional therapeutic effects were observed even by SIV-PEDF, or SIV-FGF-2 alone and, moreover, both SIV-PEDF and SIV-FGF-2 showed higher therapeutic effects.


CONCLUSIONS
These synergistic rescues of retinitis pigmentosa (RP) model animals are the 'proof concept' that the 'dual' expression of hPEDF and hFGF-2 dramatically improved therapeutic efficacy by keeping lower titers. This strategy may contribute to safer and more effective gene therapy for RP.
Miyazaki
Masanori
M
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ikeda
Yasuhiro
Y
Yonemitsu
Yoshikazu
Y
Goto
Yoshinobu
Y
Kohno
Ri-ichiro
R
Murakami
Yusuke
Y
Inoue
Makoto
M
Ueda
Yasuji
Y
Hasegawa
Mamoru
M
Tobimatsu
Shozo
S
Sueishi
Katsuo
K
Ishibashi
Tatsuro
T
D000818:Animals; D004195:Disease Models, Animal; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics* / Q000627:therapeutic use; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000627:therapeutic use; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics* / Q000627:therapeutic use; D051381:Rats; D012174:Retinitis Pigmentosa / Q000628:therapy*; D015843:Serpins / Q000235:genetics* / Q000627:therapeutic use; D015302:Simian Immunodeficiency Virus / Q000235:genetics*; D019076:Transgenes; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D016222:Fibroblast Growth Factor 2; D049452:Green Fluorescent Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C485184:enhanced green fluorescent protein