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S. Kjellstrom, Y. Zeng, Y. Takada, R. Bush, P. Sieving; Long Term Retinal Rescue in Retinoschisis Mouse Model by AAV-Gene Transfer. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4615.
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© ARVO (1962-2015); The Authors (2016-present)
X-linked juvenile retinoschisis (XLRS) causes macular degeneration characterized by delamination of the inner retinal layers and an electronegative ERG from relative loss of the b-wave. XLRS is considered to be slowly progressive in younger age and relatively stable into older age, although definitive clinical natural history is scarce. We characterized the natural history of a mouse RS genetic knockout model, and evaluated the longer term effects of retinal rescue following AAV (2/2)-CMV-Rs1h gene delivery.
Scotopic Ganzfeld ERGs were recorded from 44 male hemizygous Rs1h-KO (RS-KO) and 44 male wild type C57bl/6 (WT) mice at 6 ages between 1 - 16 months. Rod outer segment (ROS) length was measured and photoreceptor ONL cell numbers were counted. One eye each of p14 RS-KO mice was injected with AAV (2/2)-CMV-Rs1h, and retinal histology and ERGs were analyzed out to 14 months.
At 1 month, when the mouse retina is mature, RS-KO mice show reduced ERG a- and b- waves amplitudes (33% and 50% respectively). A-wave amplitudes then show a steady amplitude decline over 8 months, followed by a second phase of slower decline. ERG b-wave amplitudes declined rapidly with 50% loss by 4 months, but then plateaued up to 8 months. Half the remaining b-wave amplitude was lost by 16 months. ONL cell counts in 1 month old RS-KO mice remained nearly normal but nuclei were clearly disorganized. ONL cell count then dropped rapidly up to 8 months in parallel with the a-wave. ROS were shortened and not well aligned. Surprisingly, the intraretinal cavities seen in younger retinas were reduced in size and numbers in older animals. After intravitreal injection of AAV (2/2)-CMV-Rs1h at age p14, the RS-KO mice showed structural rescue with improved rod outer and inner segment integrity and less photoreceptor cell loss out to 14 months. ERG amplitudes in some treated mice were comparable to untreated 1 month old RS-KO mice.
Natural history of RS-KO mice showed considerable heterogeneity across age, with variable ERG amplitudes and retinal morphology. This is consistent with human clinical XLRS which displays a wide range in phenotypic severity, even within the same family and genotype. In addition to the inner retinal changes, this model shows prominent photoreceptor degeneration. This may be an important aspect of human XLRS which has not been previously emphasized. Treatment with AAV-RS1h showed long term rescue of both inner and outer retinal morphology and function, indicating gene transfer may also be effective in treating human XLRS.
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