Journal
HUMAN MOLECULAR GENETICS
Volume 22, Issue 8, Pages 1632-1642Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt013
Keywords
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Funding
- National Eye Institute [EY10609, EY018656, EY018512]
- Foundation Fighting Blindness
- Oklahoma Center for the Advancement of Science and Technology
- state of Ohio Biomedical Research Commercialization Program
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Mutations in genes in the retinal pigment epithelium (RPE) cause or contribute to debilitating ocular diseases, including Lebers congenital amaurosis (LCA). Genetic therapies, particularly adeno-associated viruses (AAVs), are a popular choice for monogenic diseases; however, the limited payload capacity of AAVs combined with the large number of retinal disease genes exceeding that capacity make the development of alternative delivery methods critical. Here, we test the ability of compacted DNA nanoparticles (NPs) containing a plasmid with a scaffold matrix attachment region (S/MAR) and vitelliform macular dystrophy 2 (VMD2) promoter to target the RPE, drive long-term, tissue-specific gene expression and mediate proof-of-principle rescue in the rpe65(/) model of LCA. We show that the S/MAR-containing plasmid exhibited reporter gene expression levels several fold higher than plasmid or NPs without S/MARs. Importantly, this expression was highly persistent, lasting up to 2 years (last timepoint studied). We therefore selected this plasmid for testing in the rpe65(/) mouse model and observe that NP or plasmid VMD2-hRPE65-S/MAR led to structural and functional improvements in the LCA disease phenotype. These results indicate that the non-viral delivery of hRPE65 vectors can result in persistent, therapeutically efficacious gene expression in the RPE.
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