Inhibition of choroidal neovascularization via brief subretinal exposure to a newly developed lentiviral vector pseudotyped with Sendai viral envelope proteins.
Lentiviral vectors are promising tools for the treatment of chronic retinal diseases, including age-related macular degeneration (AMD), as they enable stable transgene expression. On the other hand, Sendai virus (SeV) vectors provide the unique advantage of rapid gene transfer. Here we show that novel simian immunodeficiency viral vectors pseudotyped with SeV envelope proteins (SeV-F/HN-SIV) achieved rapid, efficient, and long-lasting gene transfer in the mouse retina. Subretinal exposure to SeV-F/HN-SIV vectors for only a few minutes resulted in high-level gene transfer to the retinal pigment epithelium, whereas several hours were required for gene transfer by standard vesicular stomatitis virus G-pseudotyped SIV vectors. Transgene expression continued over a 1-year period. SeV-F/HN-SIV vector-mediated retinal overexpression of soluble Fms-like tyrosine kinase-1 (sFlt-1) or pigment epithelium-derived factor (PEDF) significantly suppressed laser-induced choroidal neovascularization (CNV). Histologically, 6-month-long sustained overexpression of PEDF did not adversely affect the retina; however, that with sFlt-1 resulted in photoreceptor degeneration associated with choroidal circulation defects. These data demonstrate that brief subretinal administration of SeV-F/HN-SIV vectors may facilitate safe and efficient retinal gene transfer, and suggest the therapeutic potential of PEDF with a higher safety profile for treating CNV in AMD patients.
Murakami
Yusuke
Y
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan.
Ikeda
Yasuhiro
Y
Yonemitsu
Yoshikazu
Y
Miyazaki
Masanori
M
Inoue
Makoto
M
Hasegawa
Mamoru
M
Sueishi
Katsuo
K
Ishibashi
Tatsuro
T
D000818:Animals; D002460:Cell Line; D020256:Choroidal Neovascularization / Q000628:therapy* / Q000821:virology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000378:metabolism / Q000821:virology; D012160:Retina / Q000378:metabolism / Q000821:virology*; D029082:Sendai virus / Q000235:genetics* / Q000378:metabolism*; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D049452:Green Fluorescent Proteins; D008156:Luciferases; D009414:Nerve Growth Factors; D015843:Serpins; D014759:Viral Envelope Proteins; D000099174:Pigment Epithelium-Derived Factor