title: DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice.
abstract: Mutations in the photoreceptor-specific flippase ABCA4 are associated with Stargardt disease and many other forms of retinal degeneration that currently lack curative therapies. Gene replacement is a logical strategy for ABCA4-associated disease, particularly given the current success of traditional viral-mediated gene delivery, such as with adeno-associated viral (AAV) vectors. However, the large size of the ABCA4 cDNA (6.8 kbp) has hampered progress in the development of genetic treatments. Nonviral DNA nanoparticles (NPs) can accommodate large genes, unlike traditional viral vectors, which have capacity limitations. We utilized an optimized DNA NP technology to subretinally deliver ABCA4 to Abca4-deficient mice. We detected persistent ABCA4 transgene expression for up to 8 months after injection and found marked correction of functional and structural Stargardt phenotypes, such as improved recovery of dark adaptation and reduced lipofuscin granules. These data suggest that DNA NPs may be an excellent, clinically relevant gene delivery approach for genes too large for traditional viral vectors.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Zongchao
authors.initials: Z
authors.lastname: Han
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Conley
authors.forename: Rasha S
authors.initials: RS
authors.lastname: Makkia
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cooper
authors.forename: Muna I
authors.initials: MI
authors.lastname: Naash
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics / Q000628:therapy*; D004247:DNA / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D056965:Injections, Intraocular; D008062:Lipofuscin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053758:Nanoparticles / Q000008:administration & dosage*; D010641:Phenotype; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology; D019076:Transgenes
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D008062:Lipofuscin; D004247:DNA