title: Targeted intraceptor nanoparticle therapy reduces angiogenesis and fibrosis in primate and murine macular degeneration.
abstract: Monthly intraocular injections are widely used to deliver protein-based drugs that cannot cross the blood-retina barrier for the treatment of leading blinding diseases such as age-related macular degeneration (AMD). This invasive treatment carries significant risks, including bleeding, pain, infection, and retinal detachment. Further, current therapies are associated with a rate of retinal fibrosis and geographic atrophy significantly higher than that which occurs in the described natural history of AMD. A novel therapeutic strategy which improves outcomes in a less invasive manner, reduces risk, and provides long-term inhibition of angiogenesis and fibrosis is a felt medical need. Here we show that a single intravenous injection of targeted, biodegradable nanoparticles delivering a recombinant Flt23k intraceptor plasmid homes to neovascular lesions in the retina and regresses CNV in primate and murine AMD models. Moreover, this treatment suppressed subretinal fibrosis, which is currently not addressed by clinical therapies. Murine vision, as tested by OptoMotry, significantly improved with nearly 40% restoration of visual loss induced by CNV. We found no evidence of ocular or systemic toxicity from nanoparticle treatment. These findings offer a nanoparticle-based platform for targeted, vitreous-sparing, extended-release, nonviral gene therapy.
authors: Moran Eye Center, University of Utah, Salt Lake City, Utah 84132, United States.
authors: Ling
authors: L
authors: Luo
authors: Xiaohui
authors: X
authors: Zhang
authors: Yoshio
authors: Y
authors: Hirano
authors: Puneet
authors: P
authors: Tyagi
authors: Péter
authors: P
authors: Barabás
authors: Hironori
authors: H
authors: Uehara
authors: Tadashi R
authors: TR
authors: Miya
authors: Nirbhai
authors: N
authors: Singh
authors: Bonnie
authors: B
authors: Archer
authors: Yureeda
authors: Y
authors: Qazi
authors: Kyle
authors: K
authors: Jackman
authors: Subrata K
authors: SK
authors: Das
authors: Thomas
authors: T
authors: Olsen
authors: Srinivas R
authors: SR
authors: Chennamaneni
authors: Brian C
authors: BC
authors: Stagg
authors: Faisal
authors: F
authors: Ahmed
authors: Lyska
authors: L
authors: Emerson
authors: Kristen
authors: K
authors: Zygmunt
authors: Ross
authors: R
authors: Whitaker
authors: Christina
authors: C
authors: Mamalis
authors: Wei
authors: W
authors: Huang
authors: Guangping
authors: G
authors: Gao
authors: Sangly P
authors: SP
authors: Srinivas
authors: David
authors: D
authors: Krizaj
authors: Judit
authors: J
authors: Baffi
authors: Jayakrishna
authors: J
authors: Ambati
authors: Uday B
authors: UB
authors: Kompella
authors: Balamurali K
authors: BK
authors: Ambati
mesh_terms: D000818:Animals; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D005355:Fibrosis; D015316:Genetic Therapy / Q000379:methods*; D000882:Haplorhini; D008268:Macular Degeneration / Q000628:therapy*; D051379:Mice; D053769:Nanocapsules / Q000008:administration & dosage*; D009389:Neovascularization, Pathologic / Q000628:therapy*; D012160:Retina / Q000473:pathology*; D016896:Treatment Outcome; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
chemical_list: D053769:Nanocapsules; D004247:DNA; D040281:Vascular Endothelial Growth Factor Receptor-1