POD nanoparticles expressing GDNF provide structural and functional rescue of light-induced retinal degeneration in an adult mouse.
Peptide for ocular delivery (POD) is a novel cationic cell-penetrating peptide (CPP) which, when conjugated with polyethylene glycol (PEG-POD), can deliver plasmid DNA to the retinal pigment epithelium (RPE) of adult murine retina. PEG-POD nanoparticles containing an expression cassette for glial cell line-derived neurotrophic factor (PEG-POD~GDNF) were investigated for their ability to inhibit light-induced photoreceptor apoptosis. PEG-POD~GDNF, control nanoparticles, or buffer were injected into the subretinal space of adult murine retina and retinal degeneration induced by blue light. Animals injected with PEG-POD~GDNF showed a significant reduction (3.9-7.7 fold) in apoptosis relative to control-injected animals. The thickness of the outer nuclear layer (ONL) of the superior retina of PEG-POD~GDNF-injected eyes was significantly greater (23.6-39.3%) than control-injected retina 14 days post-light treatment. PEG-POD~GDNF-injected eyes showed a 27-39% greater functional response relative to controls, as measured by electroretinogram (ERG) 7 days post-light treatment. This is one of only two studies demonstrating histological and functional rescue of a mouse model of retinal degeneration following nonviral administration of a transgene into adult retina. Although rescue is short lived for clinical application, this study represents an important step in the development of nonviral gene therapy for retinal diseases.
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Sarah P
SP
Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Cashman
Siobhan M
SM
Kumar-Singh
Rajendra
R
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D016503:Drug Delivery Systems; D004596:Electroretinography; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D008027:Light / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D010446:Peptide Fragments / Q000627:therapeutic use; D011092:Polyethylene Glycols; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D051381:Rats; D012160:Retina / Q000528:radiation effects*; D012162:Retinal Degeneration / Q000209:etiology / Q000473:pathology / Q000628:therapy*
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D010446:Peptide Fragments; D011092:Polyethylene Glycols; D020169:Caspases