title: Gene therapy for Stargardt disease associated with ABCA4 gene.
abstract: Mutations in the photoreceptor-specific flippase ABCA4 lead to accumulation of the toxic bisretinoid A2E, resulting in atrophy of the retinal pigment epithelium (RPE) and death of the photoreceptor cells. Many blinding diseases are associated with these mutations including Stargardt's disease (STGD1), cone-rod dystrophy, retinitis pigmentosa (RP), and increased susceptibility to age-related macular degeneration. There are no curative treatments for any of these dsystrophies. While the monogenic nature of many of these conditions makes them amenable to treatment with gene therapy, the ABCA4 cDNA is 6.8 kb and is thus too large for the AAV vectors which have been most successful for other ocular genes. Here we review approaches to ABCA4 gene therapy including treatment with novel AAV vectors, lentiviral vectors, and non-viral compacted DNA nanoparticles. Lentiviral and compacted DNA nanoparticles in particular have a large capacity and have been successful in improving disease phenotypes in the Abca4 (-/-) murine model. Excitingly, two Phase I/IIa clinical trials are underway to treat patients with ABCA4-associated Startgardt's disease (STGD1). As a result of the development of these novel technologies, effective therapies for ABCA4-associated diseases may finally be within reach.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 781, 73104, Oklahoma City, OK, USA, Zongchao-han@ouhsc.edu.
authors.forename: Zongchao
authors.initials: Z
authors.lastname: Han
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Conley
authors.forename: Muna I
authors.initials: MI
authors.lastname: Naash
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008268:Macular Degeneration / Q000235:genetics / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D053758:Nanoparticles / Q000627:therapeutic use*; D000080362:Stargardt Disease
chemical_list: D018528:ATP-Binding Cassette Transporters; C512841:Abca4 protein, mouse