Long-term expression of glial cell line-derived neurotrophic factor slows, but does not stop retinal degeneration in a model of retinitis pigmentosa.
Retinitis pigmentosa is a group of diseases in which one of hundreds of mutations causes death of rod photoreceptor cells and then cones gradually die from oxidative damage. As different mutations cause rod cell death by different mechanisms, mutation-specific treatments are needed. Another approach is to use a neurotrophic factor to promote photoreceptor survival regardless of the mechanism of cell death, and previous studies have demonstrated encouraging short-term results with gene transfer of glial cell line-derived neurotrophic factor (GDNF). We generated rd10 mice with doxycycline-inducible expression of GDNF in photoreceptors (Tet/IRBP/GDNF-rd10 mice) or retinal pigmented epithelial cells (Tet/VMD2/GDNF-rd10 mice). In doxycycline-treated Tet/IRBP/GDNF-rd10 mice, there was a 9.3 × 10(4) -fold increase in Gdnf mRNA at P35 and although it decreased over time, it was still increased by 9.4 × 10(3) -fold at P70. Gdnf mRNA was increased 4.5 × 10(2) -fold in doxycycline-treated Tet/VMD2/GDMF-rd10 mice at P35 and was not significantly decreased at P70. GDNF protein levels were increased about 2.3-fold at P35 and 30% at P70 in Tet/IRBP/GDNF-rd10 mice, and in Tet/VMD2/GDNF-rd10 mice they were increased 30% at P35 and not significantly increased at P70. Despite the difference in expression, Tet/IRBP/GDNF-rd10 and Tet/VMD2/GDNF-rd10 mice had comparable significant increases in outer nuclear layer thickness and mean photopic and scotopic ERG b-wave amplitudes compared with rd10 mice at P35 which decreased, but was still significant at P70. Compared with rd10 mice, Tet/IRBP/GDNF-rd10 and Tet/VMD2/GDNF-rd10 mice had comparable significant improvements in cone density at P50 that decreased, but were still significant at P70. These data indicate that despite a large difference in expression of GDNF, Tet/IRBP/GDNF-rd10 and Tet/VMD2/GDNF-rd10 provide comparable slowing of photoreceptor degeneration, but cannot stop the degeneration.
Departments of Ophthalmology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Masayuki
M
Ohnaka
Katsuaki
K
Miki
Yuan-Yuan
YY
Gong
Rebecca
R
Stevens
Takeshi
T
Iwase
Sean F
SF
Hackett
Peter A
PA
Campochiaro
D000367:Age Factors; D000818:Animals; D000075002:Bestrophins; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D012162:Retinal Degeneration / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000150:complications* / Q000235:genetics*; D012177:Retinol-Binding Proteins / Q000235:genetics; D000099214:Retinol-Binding Proteins, Interstitial
D000075002:Bestrophins; D004318:Doxycycline; D005136:Eye Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007473:Ion Channels; D012333:RNA, Messenger; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C491856:Best1 protein, mouse