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PloS one2022; 17(8); e0270972; doi: 10.1371/journal.pone.0270972

Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy.

Abstract: 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.
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Publication Date: 2022-08-18 PubMed ID: 35980983PubMed Central: PMC9387812DOI: 10.1371/journal.pone.0270972Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study analyzes the role of adeno-associated virus gene therapy in treating equine recurrent uveitis (ERU), a vision-threatening disease affecting horses worldwide. The results demonstrate that AAV-Equine-IL10 can effectively reduce inflammation and inhibit ERU.

Introduction

  • Equine recurrent uveitis (ERU) is a serious disease of the eye that can lead to loss of vision in horses. The disease is painful, spontaneous and affects up to 25% of horse populations globally. Currently available treatments have their limitations in terms of side effects and lack of specificity, necessitating a search for more effective therapies.
  • The researchers focused on an innovative therapeutic approach using adeno-associated virus (AAV) gene therapy to trigger a natural immune tolerance mechanism through equine interleukin-10 (Equine-IL10) gene expression.

Methodology

  • The scientists carried out the study on rats where they induced experimental autoimmune uveitis (EAU) – a condition that mirrors ERU in horses. They administered intravitreal injections (IVT) of either a balanced salt solution (BSS), a low dose of AAV8-Equine-IL10 or high dose of AAV8-Equine-IL10.
  • Several types of evaluations including ophthalmic examinations, cell count assessments, histopathology, and qPCR were performed in order to gather data on disease progression.

Results

  • The findings showed that the rats treated with AAV8-Equine-IL10 had a significant decrease in clinical inflammatory scores and aqueous humor (AH) cell counts than those treated with BSS.
  • The level of cell infiltration, which is a measure of the severity of the inflammation, was significantly lower in the rats injected with AAV8-Equine-IL10 as compared to the BSS group.
  • Moreover, the AAV8-Equine-IL10 gene therapy led to the expression of Equine-IL10 cDNA in various parts of the eye including the ciliary body, retina, cornea, and optic nerve.

Conclusion

  • This study concluded that the AAV8-Equine-IL10 gene therapy was well-tolerated and was effective in preventing EAU in rats, even at the lowest administered dose.
  • The promising results of this study suggest potential benefits of further exploration of AAV gene therapy in equine and possibly human recurrent uveitis treatment.

Cite This Article

APA
Crabtree E, Uribe K, Smith SM, Roberts D, Salmon JH, Bower JJ, Song L, Bastola P, Hirsch ML, Gilger BC. (2022). Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy. PLoS One, 17(8), e0270972. https://doi.org/10.1371/journal.pone.0270972

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 17
Issue: 8
Pages: e0270972

Researcher Affiliations

Crabtree, Elizabeth
  • Department of Clinical Sciences, North Carolina State University, Raleigh, North Carolina, United States of America.
Uribe, Katy
  • Department of Clinical Sciences, North Carolina State University, Raleigh, North Carolina, United States of America.
Smith, Sara M
  • Department of Clinical Sciences, North Carolina State University, Raleigh, North Carolina, United States of America.
Roberts, Darby
  • Department of Clinical Sciences, North Carolina State University, Raleigh, North Carolina, United States of America.
Salmon, Jacklyn H
  • Department of Clinical Sciences, North Carolina State University, Raleigh, North Carolina, United States of America.
Bower, Jacquelyn J
  • Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
  • Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Song, Liujiang
  • Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
  • Gene Therapy Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Bastola, Prabhakar
  • Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Hirsch, Matthew L
  • Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
  • Gene Therapy Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Gilger, Brian C
  • Department of Clinical Sciences, North Carolina State University, Raleigh, North Carolina, United States of America.
  • Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States of America.

MeSH Terms

  • Animals
  • Autoimmune Diseases
  • Dependovirus / genetics
  • Genetic Therapy
  • Horses / genetics
  • Humans
  • Interleukin-10 / genetics
  • Interleukin-10 / therapeutic use
  • Rats
  • Uveitis

Conflict of Interest Statement

The authors have declared that no competing interests exist.

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Citations

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