title: Pharmacological enhancement of ex vivo gene therapy neuroprotection in a rodent model of retinal degeneration.
abstract: OBJECTIVE
  We have previously shown the benefits of cell-based delivery of neuroprotection in a rodent model of retinitis pigmentosa (RP). In order to maximise the effectiveness of this approach, we hypothesised that this could be augmented by combination with an aminoglycoside known to limit the abnormal RNA translation seen in this model.
  
  
  METHODS
  A rhodopsin TgN S334ter-4 rat model of RP underwent daily subcutaneous injection of 12.5 μg/g gentamicin from postnatal day 5 (P5). At P21, selected rats also underwent intravitreal injection of cells genetically engineered to oversecrete glial cell-derived neurotrophic factor. Histological imaging was undertaken to evaluate photoreceptor survival at P70 and compared with images from untreated TgN S334ter-4 rats and control Sprague-Dawley rats.
  
  
  RESULTS
  Statistically significant (p < 0.05) improvements in outer retinal indices were seen with this combination strategy when compared with results in rats treated with individual therapies alone. This improvement was most apparent in the peripheral retina, where the greatest degeneration was observed.
  
  
  CONCLUSIONS
  We have shown that the combination of neuroprotection plus aminoglycoside read-through in an animal model of retinal degeneration improved the histological appearance of the retina such that it was statistically indistinguishable from unaffected controls. Further functional and longitudinal studies of this approach are warranted.
authors.affiliation: Department of Ophthalmology and Visual Science, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. kge30@interchange.ubc.ca
authors.forename: Kevin
authors.initials: K
authors.lastname: Gregory-Evans
authors.forename: Kelvin
authors.initials: K
authors.lastname: Po
authors.forename: Francis
authors.initials: F
authors.lastname: Chang
authors.forename: Cheryl Y
authors.initials: CY
authors.lastname: Gregory-Evans
mesh_terms: D000818:Animals; D002452:Cell Count; D002470:Cell Survival; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D015316:Genetic Therapy; D005822:Genetic Vectors; D005839:Gentamicins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D007279:Injections, Subcutaneous; D011500:Protein Synthesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000628:therapy*; D014162:Transfection
chemical_list: D005839:Gentamicins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D011500:Protein Synthesis Inhibitors