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William A Beltran, Artur V Cideciyan, Simone Iwabe, Alfred S Lewin, Malgorzata Swider, Jose M Guzman, Sanford L Boye, William W Hauswirth, Samuel G Jacobson, Gustavo D Aguirre, RC; Gene therapy for RPGR-XLRP in a canine model results in retained photoreceptors and vision for at least 2.5 years. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2588. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
RPGR gene augmentation successfully rescues photoreceptors when delivered at early, mid, and late stages of disease in the canine XLPRA2 model of XLRP, one of the most common and severe forms of retinal degeneration in man (Beltran et al. ARVO 2014). We now report on the long-term (up to 2.5 years) follow-up of these treated RPGR mutant dogs.
Seven RPGR mutant dogs that were unilaterally treated with a subretinal injection (70-150 μl) of an AAV2/5 vector construct (1.51 x1011 vg/ml) carrying full-length human RPGR1-ORF15 cDNA under control of a hIRBP promoter at early (age=5 wks; ONL near normal thickness), mid (age=12 wks; ONL=~60% of normal) and late (age=26 wks: ONL=~50-40% of normal) stages of disease were followed up to 152 wks of age. Photoreceptor structure and function was assessed by SD-OCT and ERG. Rod-mediated visual behavior of dogs from the late-disease treatment group was assessed between 149-152 wks of age under scotopic conditions in a custom-made Y maze by using an opaque corneal occluder to test separately the AAV-RPGR and contralateral BSS treated eyes.
While early intervention resulted in better ONL preservation, statistically significant ONL rescue was still detectable by OCT at 130 weeks of age in the treated areas of dogs from all 3 groups including those treated at late-stage disease. Longitudinal analysis of OCT data showed that after an initial reduction, ONL thickness stabilized in the treated areas, while in the untreated regions it followed the natural course of XLPRA2 disease progression. No ONL preservation was seen in BSS control eyes. Retinal function assessed by ERG showed higher amplitudes in all AAV-RPGR treated eyes than in contralateral BSS-injected eyes at 131 weeks of age. Objective vision testing of 2 dogs treated at late stage disease showed at 152 wks of age statistically significant improved performance in the Y maze for the AAV-RPGR treated eyes.
These results confirm the long-term and stable rescue of photoreceptor structure and function following subretinal RPGR gene augmentation therapy delivered at early, mid and late stages of disease. In addition, with disease progression and severe visual impairment in the control eyes we are now able to demonstrate in ~ 3 year-old XLPRA2 dogs the benefit of RPGR gene augmentation on visual function even when therapy was delivered at late stage disease.
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