Journal
MOLECULAR THERAPY
Volume 28, Issue 1, Pages 293-303Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2019.09.010
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Funding
- Harrington Discovery Institute
- NEI [R24-EY-024864, R24-EY-027283]
- Canadian Institute for Advanced Research (CIFAR)
- Alcon Research Institute (ARI)
- Foundation of Fighting Blindness
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Stargardt disease (STGD) is an autosomal recessive retinal disorder caused by a monogenic ABCA4 mutation. Currently, there is no effective therapy to cure Stargardt disease. The replacement of mutated ABCA4 with a functional gene remains an attractive strategy. In this study, we have developed a non-viral gene therapy using nanoparticles self-assembled by a multifunctional pH-sensitive amino lipid ECO and a therapeutic ABCA4 plasmid. The nanoparticles mediated efficient intracellular gene transduction in wild-type (WT) and Abca4(-/-) mice. Specific ABCA4 expression in the outer segment of photoreceptors was achieved by incorporating a rhodopsin promoter into the plasmids. The ECO/pRHO-ABCA4 nanoparticles induced substantial and specific ABCA4 expression for at least 8 months, 35% reduction in A2E accumulation on average, and a delayed Stargardt disease progression for at least 6 months in Abca4(-/-) mice. ECO/plasmid nanoparticles constitute a promising non-viral gene therapy platform for Stargardt disease and other visual dystrophies.
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