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Rajendra Kumar-Singh, Christina Binder, Siobhan Cashman; Increased Longevity of Rescue of Light-Induced Retinal Damage in an Adult Mouse Using Peptide for Ocular Delivery (POD) as a Gene Transfer Vector. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5582.
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© ARVO (1962-2015); The Authors (2016-present)
Nonviral gene delivery is a promising approach to gene therapy for ocular diseases, such as Retinitis Pigmentosa (RP) and Age-Related Macular Degeneration (AMD). The use of nonviral systems has been hampered by limited efficiency of gene transfer and short-lived duration of expression. Using a pegylated cationic peptide, PEGPOD, to deliver a transgene expressing GDNF (glial-derived neurotrophic factor), we have previously shown rescue of light-induced retinal degeneration in an adult mouse up to 18 days post-transgene delivery. In this study, we determined factors necessary to significantly increase duration of expression and rescue.
PEGPOD was complexed with a plasmid expressing luciferase and different amounts of the complex injected into the subretinal space of Balb/c mice. Luciferase expression was quantified up to 15 weeks post-injection. Once the optimal amount of plasmid was determined, PEGPOD was complexed with a GDNF-expressing plasmid and injected into the subretinal space of Balb/c mice. Mice were subjected to 450-nm blue light at 14, 30, and 70 days post-injection. Electroretinograms (ERG) and thickness of outer nuclear layer (ONL) were measured 7 days post-light treatment.
Reduced dose of the PEGPOD/DNA complex resulted in expression of the luciferase up to 10 weeks post-injection. When PEGPOD was complexed with GDNF (PEGPOD/GDNF) and injected 30 days prior to light treatment, significant functional and anatomical rescue was observed. A- and B- wave amplitudes of mice injected 30 days prior to light treatment were increased by 77% and 65%, respectively, relative to control-injected mice. While functional rescue of mice injected with PEGPOD/GDNF 70 days prior to light treatment was not significant, ONL thickness of eyes injected with PEGPOD/GDNF was significantly increased by 25% relative to control-injected eyes.
PEGPOD/GDNF complexes show biologically significant expression in retinas of a mouse model of light-induced degeneration up to 70 days post-injection. This study illustrates the potential of PEGPOD/GDNF to mediate long-term rescue of retinal diseases such as RP and AMD, and asserts the need for consideration of this nonviral gene transfer system as a clinically viable approach to treatment of these devastating diseases.
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