Non-viral Gene Therapy for Stargardt Disease with ECO/pRHO-ABCA4 Self-Assembled Nanoparticles

• Published in: Molecular therapy Vol. 28; no. 1; pp. 293 - 303
• Main Authors: Sun, Da, Schur, Rebecca M., Sears, Avery E., Gao, Song-Qi, Vaidya, Amita, Sun, Wenyu, Maeda, Akiko, Kern, Timothy, Palczewski, Krzysztof, Lu, Zheng-Rong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-01-2020; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: ABCA4; Animals; ATP-Binding Cassette Transporters - administration & dosage; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Cell Line; Cytomegalovirus; Cytotoxicity; Deoxyribonucleic acid; Disease Models, Animal; DNA; Drug Delivery Systems - methods; ECO; Gene expression; Gene therapy; Genetic Therapy - methods; Hereditary diseases; Humans; Lipopeptides - administration & dosage; Lipopeptides - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy; Nanoparticles; Nanoparticles - chemistry; non-viral delivery; Original; pH effects; Photoreceptor Cells - metabolism; Photoreceptors; Plasmids; Plasmids - genetics; Plasmids - therapeutic use; Retina; Retinal Pigment Epithelium - cytology; Retinal Pigment Epithelium - metabolism; Rhodopsin; Rhodopsin - administration & dosage; Rhodopsin - genetics; Stargardt disease; Stargardt Disease - genetics; Stargardt Disease - therapy; Transfection; ECO; gene therapy; non-viral delivery; Stargardt disease; ABCA4
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.09.010

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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Stargardt disease is a genetic retinal disorder caused by ABCA4 mutation. Currently, there is no effective therapy to cure it. Sun et al. developed a self-assembled nanoparticle-based gene therapy using a pH-sensitive amino lipid ECO and tissue-specific ABCA4 plasmid, which mediated substantial tissue-specific ABCA4 expression and disease rescue for at least 6 months.