The purpose of the present study was to test the therapeutic efficiency and safety of compacted-
DNA nanoparticle-mediated gene delivery into the subretinal space of a juvenile mouse model of
retinitis pigmentosa. Nanoparticles containing the mouse
opsin promoter and wild-type mouse Rds gene were injected subretinally into mice carrying a haploinsufficiency mutation in the
retinal degeneration slow (rds(+ or -)) gene at postnatal day (P)5 and 22. Control mice were either injected with saline, injected with uncompacted naked plasmid
DNA carrying the Rds gene, or remained untreated. Rds
mRNA levels peaked at postinjection day 2 to 7 (PI-2 to PI-7) for P5
injections, stabilized at levels 2-fold higher than in uninjected controls for both P5 and P22
injections, and remained elevated at the latest time point examined (PI-120). Rod function (measured by electroretinography) showed modest but statistically significant improvement compared with controls after both P5 and P22
injections. Cone function in nanoparticle-injected eyes reached wild-type levels for both ages of
injections, indicating full prevention of cone degeneration. Ultrastructural examination at PI-120 revealed significant improvement in outer segment structures in P5 nanoparticle-injected eyes, while P22 injection had a modest structural improvement. There was no evidence of macrophage activation or induction of
IL-6 or
TNF-alpha mRNA in P5 or P22 nanoparticle-dosed eyes at either PI-2 or PI-30. Thus, compacted-
DNA nanoparticles can efficiently and safely drive gene expression in both mitotic and postmitotic photoreceptors and retard degeneration in this model. These findings, using a clinically relevant treatment paradigm, illustrate the potential for application of nanoparticle-based gene replacement
therapy for treatment of human
retinal degenerations.-Cai, X., Conley, S. M., Nash, Z., Fliesler, S. J., Cooper, M. J., Naash, M. I. Gene delivery to mitotic and postmitotic photoreceptors via compacted
DNA nanoparticles results in improved phenotype in a mouse model of
retinitis pigmentosa.