title: Neuroprotection of retinal ganglion cells in DBA/2J mice with GDNF-loaded biodegradable microspheres.
abstract: This study aims to promote long-term retinal ganglion cell (RGC) survival in a spontaneous glaucoma model by injecting slow-release Poly(DL-lactide-co-glycolide) (PLGA) microspheres containing glial cell line-derived neurotrophic factor (GDNF) into the vitreous. Microspheres (1 microL) suspended in PBS were injected in ipsilateral eyes while contralateral eyes served as untreated controls. Mice were injected at 2 months intervals (1-4 injections) depending on the protocol. ELISA assay indicated a cumulative GDNF release of 35.4 ng/mg over 71 days. The release was nonlinear with an initial burst of over 50%. Mice displayed a 30% drop in RGC density by 8 months (p = 0.013) and 80% drop by 10 months (p < 0.01). GDNF delivery increased RGC survival in all groups. Mice receiving early treatment showed up to 3.5 times greater RGC density than untreated mice at 15 months survival (p < 0.05). No significant effect was found in sham or lens injury groups. Microsphere-delivered GDNF significantly increases long-term RGC survival in a spontaneous glaucoma model, although the nonlinear release kinetics suggest that burst release may play a role in this rescue. Neuroprotection with slow-release polymers with improved release kinetics should be further studied as a potential therapy for glaucoma and other diseases involving the loss of central nervous system neurons.
authors.affiliation: Schepens Eye Research Institute, Harvard Medical School, 20 Staniford Street, Boston, Massachusetts 02114, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Ward
authors.forename: A
authors.initials: A
authors.lastname: Khoobehi
authors.forename: E B
authors.initials: EB
authors.lastname: Lavik
authors.forename: R
authors.initials: R
authors.lastname: Langer
authors.forename: M J
authors.initials: MJ
authors.lastname: Young
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage*; D007267:Injections; D019344:Lactic Acid / Q000008:administration & dosage*; D051379:Mice; D008811:Mice, Inbred DBA; D008863:Microspheres; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011100:Polyglycolic Acid / Q000008:administration & dosage*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000008:administration & dosage*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects*; D014822:Vitreous Body
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid