Anti-apoptotic effects of CNTF gene transfer on photoreceptor degeneration in experimental antibody-induced retinopathy

被引:35
作者
Adamus, G
Sugden, B
Shiraga, S
Timmers, AM
Hauswirth, WW
机构
[1] Oregon Hlth & Sci Univ, Inst Neurol Sci, Portland, OR USA
[2] Univ Florida, Dept Ophthalmol, Gainesville, FL USA
[3] Univ Florida, Powell Gene Therapy Ctr, Gainesville, FL USA
关键词
gene therapy; retinal degeneration; autoimmune retinopathy; Lewis rat; CNTF; recoverin; apoptosis; AAV; STAT3;
D O I
10.1016/S0896-8411(03)00092-1
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 anti body-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. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:121 / 129
页数:9
相关论文
共 49 条
[31]  
MUZYCZKA N, 1992, CURR TOP MICROBIOL, V158, P97
[32]   Growth factors in combination, but not individually, rescue rd mouse photoreceptors in organ culture [J].
Ogilvie, JM ;
Speck, JD ;
Lett, JM .
EXPERIMENTAL NEUROLOGY, 2000, 161 (02) :676-685
[33]  
Ohguro H, 1999, INVEST OPHTH VIS SCI, V40, P3160
[34]   Apoptosis of spinal interneurons induced by sciatic nerve axotomy in the neonatal rat is counteracted by nerve growth factor and ciliary neurotrophic factor [J].
Oliveira, ALR ;
Risling, M ;
Negro, A ;
Langone, F ;
Cullheim, S .
JOURNAL OF COMPARATIVE NEUROLOGY, 2002, 447 (04) :381-393
[35]  
Peterson WM, 2000, J NEUROSCI, V20, P4081
[36]   Pathways to photoreceptor cell death in inherited retinal degenerations [J].
Pierce, EA .
BIOESSAYS, 2001, 23 (07) :605-618
[37]   Local adenoviral-mediated expression of recombinant hirudin reduces neointima formation after arterial injury [J].
Rade, JJ ;
Schulick, AH ;
Virmani, R ;
Dichek, DA .
NATURE MEDICINE, 1996, 2 (03) :293-298
[38]   Adeno-associated virus type-2 expression of pigmented epithelium-derived factor or Kringles 1-3 of angiostatin reduce retinal neovascularization [J].
Raisler, BJ ;
Berns, KI ;
Grant, MB ;
Beliaev, D ;
Hauswirth, WW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (13) :8909-8914
[39]   CNTF VARIANTS WITH INCREASED BIOLOGICAL POTENCY AND RECEPTOR SELECTIVITY DEFINE A FUNCTIONAL SITE OF RECEPTOR INTERACTION [J].
SAGGIO, I ;
GLOAGUEN, I ;
POIANA, G ;
LAUFER, R .
EMBO JOURNAL, 1995, 14 (13) :3045-3054
[40]   Mechanism of CAR syndrome: anti-recoverin antibodies are the inducers of retinal cell apoptotic death via the caspase 9- and caspase 3-dependent pathway [J].
Shiraga, S ;
Adamus, G .
JOURNAL OF NEUROIMMUNOLOGY, 2002, 132 (1-2) :72-82