Anti-apoptotic effects of CNTF gene transfer on photoreceptor degeneration in experimental antibody-induced retinopathy.
Autoantibodies against recoverin are found in the sera of patients with cancer-associated retinopathy syndrome, a paraneoplastic disease associated with retinal degeneration. We have previously shown that anti-recoverin autoantibodies induced photoreceptor apoptotic cell death after injection into the vitreous of Lewis rats. Ciliary neurotrophic factor (CNTF) has been shown to promote the survival of a number of neuronal cell types, including photoreceptors. In this study, we examined whether an adeno-associated virus (AAV)-mediated delivery of gene encoding the human CNTF protected photoreceptor cells from anti-recoverin antibody-induced death. One month after subretinal injection of the AAV-CNTF gene into one eye and a control vector into the other eye, an anti-recoverin antibody was injected to induce retinal cell death in Lewis rats. Subretinal administration of the virus led to an efficient transduction of photoreceptors, as indicated by immunostaining of retinas with anti-CNTF. Histological examination of the corresponding retinas showed that photoreceptor cells were significantly protected from apoptotic death in the CNTF-treated eyes. CNTF treatment of the retinas resulted in a time-dependent activation of STAT 3. The present study shows that an AAV-mediated delivery of CNTF may protect photoreceptors from antibody-induced cell death through the activation of STAT3 and the suppression of caspase 3 activity, a key caspase leading to apoptosis. Thus, CNTF may be a useful treatment for human antibody-mediated retinal degeneration.
Adamus
Grazyna
G
Neurological Sciences Institute, Oregon Health & Science University, Portland, OR, USA. adamusg@ohsu.edu
Sugden
Brad
B
Shiraga
Sharon
S
Timmers
Adrian M
AM
Hauswirth
William W
WW
D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000633:toxicity*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000628:therapy; D002135:Calcium-Binding Proteins / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D005136:Eye Proteins; D015316:Genetic Therapy; D005822:Genetic Vectors; D051597:Hippocalcin; D006801:Humans; D008074:Lipoproteins; D008954:Models, Biological; D009419:Nerve Tissue Proteins; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D020801:Receptor, Ciliary Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D051603:Recoverin; D012160:Retina / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014161:Transduction, Genetic
D001323:Autoantibodies; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D008074:Lipoproteins; D009419:Nerve Tissue Proteins; C496731:RCVRN protein, human; C496733:Rcvrn protein, rat; D020801:Receptor, Ciliary Neurotrophic Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; D015534:Trans-Activators; D051603:Recoverin; D051597:Hippocalcin