Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy.
Equine recurrent uveitis (ERU) is a spontaneous, painful, and vision threatening disease affecting up to 25% of equine populations worldwide. Current treatments of ERU are non-specific and have many side effects which limits them to short-term use. In order to develop an effective therapy for ERU, w...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0270972 |
| _version_ | 1828150441546874880 |
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| author | Elizabeth Crabtree Katy Uribe Sara M Smith Darby Roberts Jacklyn H Salmon Jacquelyn J Bower Liujiang Song Prabhakar Bastola Matthew L Hirsch Brian C Gilger |
| author_facet | Elizabeth Crabtree Katy Uribe Sara M Smith Darby Roberts Jacklyn H Salmon Jacquelyn J Bower Liujiang Song Prabhakar Bastola Matthew L Hirsch Brian C Gilger |
| author_sort | Elizabeth Crabtree |
| collection | DOAJ |
| description | Equine recurrent uveitis (ERU) is a spontaneous, painful, and vision threatening disease affecting up to 25% of equine populations worldwide. Current treatments of ERU are non-specific and have many side effects which limits them to short-term use. In order to develop an effective therapy for ERU, we investigated the use of adeno-associated virus (AAV) gene therapy, exploiting a natural immune tolerance mechanism induced by equine interleukin-10 (Equine-IL10). The purpose of this study was to evaluate the therapeutic efficacy of a single intravitreal (IVT) dose of AAV8-Equine-IL10 gene therapy for inhibition of experimental autoimmune uveitis (EAU) in rats. Each rat was dosed intravitreally (IVT) in both eyes with either balanced salt solution (BSS) (control; n = 4), AAV8-Equine-IL10 at a low dose (2.4x109 vg; n = 5) or high dose (2.4x1010 vg; n = 5). EAU was induced in all groups of rats 7 days after IVT injections and euthanized 21 days post-injection. Ophthalmic examination and aqueous humor (AH) cell counts were recorded with the observer blinded to the treatment groups. Histopathology and qPCR were performed on selected ocular tissues. Data presented herein demonstrate that AAV8-Equine-IL10 treated rats exhibited a significant decrease in clinical inflammatory scores and AH cell counts compared to BSS-treated EAU eyes on days 10, 12 and 14 post EAU induction at both administered vector doses. Mean cellular histologic infiltrative scores were also significantly less in AAV8-Equine-IL10 dosed rats compared to the BSS group. Intravitreal injection of AAV8-Equine-IL10 resulted in Equine-IL10 cDNA expression in the ciliary body, retina, cornea, and optic nerve in a dose-dependent manner. A single IVT injection of AAV8-Equine-IL10 appeared to be well-tolerated and inhibited EAU even at the lowest administered dose. These results demonstrate safety and efficacy of AAV8-Equine-IL10 to prevent EAU and support continued exploration of AAV gene therapy for the treatment of equine and perhaps human recurrent uveitis. |
| first_indexed | 2024-04-11T21:44:34Z |
| format | Article |
| id | doaj.art-09fa11cc71154043970cb391d0db4f03 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-11T21:44:34Z |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-09fa11cc71154043970cb391d0db4f032022-12-22T04:01:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032022-01-01178e027097210.1371/journal.pone.0270972Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy.Elizabeth CrabtreeKaty UribeSara M SmithDarby RobertsJacklyn H SalmonJacquelyn J BowerLiujiang SongPrabhakar BastolaMatthew L HirschBrian C GilgerEquine recurrent uveitis (ERU) is a spontaneous, painful, and vision threatening disease affecting up to 25% of equine populations worldwide. Current treatments of ERU are non-specific and have many side effects which limits them to short-term use. In order to develop an effective therapy for ERU, we investigated the use of adeno-associated virus (AAV) gene therapy, exploiting a natural immune tolerance mechanism induced by equine interleukin-10 (Equine-IL10). The purpose of this study was to evaluate the therapeutic efficacy of a single intravitreal (IVT) dose of AAV8-Equine-IL10 gene therapy for inhibition of experimental autoimmune uveitis (EAU) in rats. Each rat was dosed intravitreally (IVT) in both eyes with either balanced salt solution (BSS) (control; n = 4), AAV8-Equine-IL10 at a low dose (2.4x109 vg; n = 5) or high dose (2.4x1010 vg; n = 5). EAU was induced in all groups of rats 7 days after IVT injections and euthanized 21 days post-injection. Ophthalmic examination and aqueous humor (AH) cell counts were recorded with the observer blinded to the treatment groups. Histopathology and qPCR were performed on selected ocular tissues. Data presented herein demonstrate that AAV8-Equine-IL10 treated rats exhibited a significant decrease in clinical inflammatory scores and AH cell counts compared to BSS-treated EAU eyes on days 10, 12 and 14 post EAU induction at both administered vector doses. Mean cellular histologic infiltrative scores were also significantly less in AAV8-Equine-IL10 dosed rats compared to the BSS group. Intravitreal injection of AAV8-Equine-IL10 resulted in Equine-IL10 cDNA expression in the ciliary body, retina, cornea, and optic nerve in a dose-dependent manner. A single IVT injection of AAV8-Equine-IL10 appeared to be well-tolerated and inhibited EAU even at the lowest administered dose. These results demonstrate safety and efficacy of AAV8-Equine-IL10 to prevent EAU and support continued exploration of AAV gene therapy for the treatment of equine and perhaps human recurrent uveitis.https://doi.org/10.1371/journal.pone.0270972 |
| spellingShingle | Elizabeth Crabtree Katy Uribe Sara M Smith Darby Roberts Jacklyn H Salmon Jacquelyn J Bower Liujiang Song Prabhakar Bastola Matthew L Hirsch Brian C Gilger Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy. PLoS ONE |
| title | Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy. |
| title_full | Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy. |
| title_fullStr | Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy. |
| title_full_unstemmed | Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy. |
| title_short | Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy. |
| title_sort | inhibition of experimental autoimmune uveitis by intravitreal aav equine il10 gene therapy |
| url | https://doi.org/10.1371/journal.pone.0270972 |
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