Tetracycline-inducible viral interleukin-10 intraocular gene transfer, using adeno-associated virus in experimental autoimmune uveoretinitis.
Members of the adeno-associated virus (AAV) family are good candidates for the treatment of ocular diseases because of their relative lack of pathogenicity. We studied the effect of intraocular injection of AAV2-viral IL-10 (vIL-10) on retinal S-antigen-induced experimental autoimmune uveoretinitis (EAU) in Lewis rats. We demonstrated that AAV2/2-GFP injected into the vitreous body transduced the iris and ciliary body, or anterior uvea, and the retina. We showed that intravitreal injection of the AAV2/2-tetON-vIL-10 construct achieved detectable levels of vIL-10 mRNA and protein within the eye and was effective in protecting the rat retina against destruction. This protection was dependent on the level of vIL-10 present in the aqueous humor/ vitreous body. Intravitreal injection of the same construct encased within an AAV5 shell, AAV2/5-tetONvIL- 10, did not confer any degree of protection. It appeared that the AAV2/5 vectors did not transduce the anterior uvea, the site at which inflammatory cells first localize in EAU, nor the ganglion cell layer; induced low expression of vIL-10 mRNA; and did not achieve detectable levels of transgene expression in the aqueous humor/vitreous body. Local treatment with AAV2/2-tetON-vIL-10 did not dampen the systemic immune response, as determined by S-antigen-specific lymphocyte proliferation. Our results show that local intravitreal injection of AAV2/2 is an effective means by which to deliver immunoregulatory molecules into the eye during uveitis, a chronic human ocular disease.
Smith
Justine R
JR
INSERM U598, Institut Biomedical des Cordeliers, 75270 Paris, France.
Verwaerde
Claudie
C
Rolling
Fabienne
F
Naud
Marie-Christine
MC
Delanoye
Anne
A
Thillaye-Goldenberg
Brigitte
B
Apparailly
Florence
F
De Kozak
Yvonne
Y
D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects; D019393:Arrestin; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D012160:Retina / Q000187:drug effects / Q000473:pathology; D012173:Retinitis / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D013752:Tetracycline / Q000494:pharmacology; D014605:Uveitis / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*
D019393:Arrestin; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; D013752:Tetracycline