title: Repeated injections of a ciliary neurotrophic factor analogue leading to long-term photoreceptor survival in hereditary retinal degeneration.
abstract: OBJECTIVE
  To determine whether ciliary neurotrophic factor (CNTF) or brain-derived neurotrophic factor (BDNF) treatment leads to long-term photoreceptor survival in hereditary retinal degeneration.
  
  
  METHODS
  An autosomal dominant feline model of rod-cone dystrophy was used throughout the study with two normal animals. In the first experiment, intravitreal injections of a human CNTF analogue (Axokine; Regeneron Pharmaceuticals, Tarrytown, NY) were administered to one eye of each animal (n = 10) beginning on postnatal day 10 and were repeated every 4 weeks. Clinical and histopathologic examinations were performed at 5.5, 9.5, and 13.5 weeks. In the second experiment, animals (n = 17) were randomly assigned to receive intravitreal injections of either Axokine (at half the initial dose), human BDNF, or the vehicle for Axokine to one eye at 5.5 weeks. The same therapy was repeated every 4 weeks in each group. Clinical and histopathologic examinations were performed at 9.5, 13.5, and 17.5 weeks. Photoreceptor survival was assessed by cell counting. Apoptotic cells were identified by morphology and a modified TdT-dUTP terminal nick-end labeling (TUNEL) technique. In the third experiment, two normal animals were treated with Axokine as in the first experiment. Glial fibrillary acidic protein ((GFAP) immunohistochemistry was performed to assess glial cell reaction.
  
  
  RESULTS
  In the first two experiments, Axokine significantly prolonged photoreceptor survival (P < 0.01) and reduced the presence of apoptotic cells (P < 0.05) and TUNEL-positive cells (P < 0.05). In the second experiment, results in the the BDNF- and sham-injected eyes were not significantly different from those in the untreated eyes. Minimal posterior subcapsular cataract and mild retinal folds were found in all Axokine-treated eyes in both dystrophic and normal animals. These complications were milder in the second experiment when injections were started later and at a reduced dose. GFAP immunolabeling was also increased in all Axokine-treated eyes.
  
  
  CONCLUSIONS
  Axokine, but not BDNF, delays photoreceptor loss in this hereditary retinal degeneration. Repeated injections maintain the protective effect.
authors.affiliation: Department of Pathology, Institute of Ophthalmology, University College London, United Kingdom.
authors.forename: N H
authors.initials: NH
authors.lastname: Chong
authors.forename: R A
authors.initials: RA
authors.lastname: Alexander
authors.forename: L
authors.initials: L
authors.lastname: Waters
authors.forename: K C
authors.initials: KC
authors.lastname: Barnett
authors.forename: A C
authors.initials: AC
authors.lastname: Bird
authors.forename: P J
authors.initials: PJ
authors.lastname: Luthert
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002386:Cataract / Q000139:chemically induced; D002415:Cats; D002452:Cell Count / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D020934:Ciliary Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007267:Injections; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D012160:Retina / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D012174:Retinitis Pigmentosa / Q000473:pathology / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020934:Ciliary Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; C118937:axokine