Simian lentiviral vector-mediated retinal gene transfer of pigment epithelium-derived factor protects retinal degeneration and electrical defect in Royal College of Surgeons rats.
Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal diseases resulting in adult blindness caused by mutations of various genes. Although it is difficult to cure the blindness that results from these diseases, delaying the disease progression may be of great benefit, since the majority of RP diseases are seen in middle age or later. To test a gene therapy strategy for RP using a neurotrophic factor gene, we assessed the effect of simian lentivirus (SIV)-mediated subretinal gene transfer of pigment epithelium-derived factor (PEDF), a potent neurotrophic factor, during the disease progression in Royal College of Surgeons (RCS) rats, a well-accepted animal model of RP. Regional gene transfer via SIV into the peripheral subretinal space at the nasal hemisphere was performed in all animals to monitor site-specific transgene expression as well as the therapeutic effect in each retina. Gene transfer of lacZ and PEDF was observed in the regional pigment epithelium corresponding to the regional gene transfer. Histologically, PEDF gene transfer significantly protected the loss of photoreceptor cells (PCs) corresponding to the regions of the gene transfer, compared to those of control groups during the course of the experiment. The antiapoptotic effect of PEDF on PCs is likely to be a related mechanism, because a significant reduction of terminal dUTP-nicked end labeling-positive PC numbers was found in PEDF-treated eyes compared to those of the control group (P<0.05). PEDF-treated eyes also retained a significant sensitivity to light flash during the experimental course. These findings clearly show that neuroprotective gene therapy using PEDF can protect retinal degeneration and functional defects in individuals with RP.
Miyazaki
M
M
Division of Pathophysiology and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ikeda
Y
Y
Yonemitsu
Y
Y
Goto
Y
Y
Sakamoto
T
T
Tabata
T
T
Ueda
Y
Y
Hasegawa
M
M
Tobimatsu
S
S
Ishibashi
T
T
Sueishi
K
K
D000818:Animals; D017209:Apoptosis; D004596:Electroretinography; D005136:Eye Proteins; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009414:Nerve Growth Factors; D011506:Proteins / Q000235:genetics*; D051381:Rats; D011919:Rats, Inbred Strains; D012160:Retina / Q000473:pathology / Q000503:physiopathology; D012174:Retinitis Pigmentosa / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D015843:Serpins / Q000235:genetics*; D015302:Simian Immunodeficiency Virus / Q000235:genetics*; D014161:Transduction, Genetic / Q000379:methods*; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D009414:Nerve Growth Factors; D011506:Proteins; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor