Gene delivery to mitotic and postmitotic photoreceptors Via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa
| Autor: | Muna I. Naash, Shannon M. Conley, Xue Cai, Zack Nash, Steven J. Fliesler, Mark J. Cooper |
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| Rok vydání: | 2009 |
| Předmět: |
Retinal degeneration
Time Factors genetic structures Peripherins Mitosis Nerve Tissue Proteins Gene delivery Biology medicine.disease_cause Biochemistry Research Communications Mice chemistry.chemical_compound Intermediate Filament Proteins Retinal Rod Photoreceptor Cells Transduction Genetic Retinitis pigmentosa Gene expression Genetics medicine Animals Humans Promoter Regions Genetic Molecular Biology Mutation Membrane Glycoproteins Opsins medicine.diagnostic_test Interleukin-6 Tumor Necrosis Factor-alpha Macrophages Retinal DNA Genetic Therapy Macrophage Activation medicine.disease Molecular biology Disease Models Animal chemistry Retinal Cone Photoreceptor Cells Nanoparticles sense organs Haploinsufficiency Retinitis Pigmentosa Biotechnology Electroretinography |
| Zdroj: | The FASEB Journal. 24:1178-1191 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.09-139147 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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