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Berta De la Cerda, Francisco J. Diaz-Corrales, Lourdes Valdes-Sanchez, Ana Aramburu, Daniel Rodriguez-Martinez, Begoña Seijo, Andrea Pensado, Alejandro Sanchez-Barreiro, Shom Shanker Bhattacharya; PRPF31 delivery onto the retina using a nanoparticle system improves the visual acuity in a mouse model of retinal degeneration caused by A216P mutation in PRPF31 gene. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5412.
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© ARVO (1962-2015); The Authors (2016-present)
Very few therapeutical options exist today for retinal degenerative diseases. We used Prpf31 A216P/+ (KI) mice (Bujakowska et al. IOVS 2009) as a mouse model for inherited retinal disease to pre-clinically test the therapeutic activity of nanoparticle delivery of the PRPF31 gene as a treatment for the haploinsuficiency caused by the mutation. The animal model used in our study harbors the human mutation A216P in PRPF31 gene, which is known to cause retinitis pigmentosa (Vithana et al. Mol. Cell 2001). Mutations in this gene are also known to produce juvenile macular degeneration (Lu et al. PLOS one 2013).
Six-month-old C57BL/6J mice and WT littermates were anesthetized before the sub-retinal injection of 1µL of nanoparticles containing 200ng of plasmid for the expression of PRPF31 (Number of eyes, N=8) or GFP (N=6) under CMV promoter (pEGFP-N1, Clontech). Control animals were injected with 1µL of 5% glucose (N=6). One month after treatment, animals were subjected to optomotor test (OT), setting 6 frequencies from 0.031 to 0.272 cycles/degree (c/d) and 100%, 75% and 50% contrast sensitivity. Retinal structure and thickness were tested using optical coherence tomography (OCT).
Statistically significant improvement in visual acuity was found in KI treated (PRPF31-injected) mice at 100% contrast at every frequency tested (p=0.02 at 0.272 c/d), showing a positive OT response in 75±2.8% of the cases in WT control (glucose-injected) animals and 68.5±8.6 in treated KI ones, while untreated KI (GFP -injected) mice showed only 33.3±4.4% of positive OT responses. Positive responses in KI treated animals decreased alongside with decreasing contrast, but still improved compared to untreated mutant mice. OCT measure of retinal thickness for WT control mice was 216.6±6.9 µm, for KI untreated mice was 198.5±1.9 µm and for treated KI mice was 211.9±13.5 µm. Thickness of the retina was significantly increased comparing KI treated and untreated samples (p=0.04).
Nanoparticle -driven delivery of the PRPF31 gene to the subretinal space of mice has a therapeutical effect on the spatial vision (visual acuity and contrast sensitivity) and on the retinal thickness of the Prpf31 A216P/+ mouse model.
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