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Human gene therapy2019; 31(1-2); 110-118; doi: 10.1089/hum.2019.195

Sustained Interleukin-10 Transgene Expression Following Intra-Articular AAV5-IL-10 Administration to Horses.

Abstract: Joint trauma leads to post-traumatic inflammation with upregulation of inflammatory cytokines and degradative enzymes. If severe enough, this response can lead to irreversible post-traumatic osteoarthritis. Interleukin-10 (IL-10), a cytokine with potent anti-inflammatory effects, has been shown to have chondroprotective effects. A gene therapy approach using a vector to overexpress IL-10 in the joint represents a feasible method of delivering sustained high doses of IL-10 to post-traumatic joints. We hypothesized that an AAV5 vector overexpressing IL-10 would result in rapid and sustained IL-10 expression following direct intra-articular injection and that this increase would not be reflected in systemic circulation. In addition, we hypothesized that intra-articular AAV5-IL-10 injection would not induce a local inflammatory response. Twelve horses were assigned to either treatment (AAV5-IL-10-injected) or control (PBS-injected) groups. Middle carpal joints were injected with 10 vector genomes/joint or phosphate-buffered saline (PBS) alone (3 mL). Serial synovial fluid samples were analyzed for inflammatory changes, IL-10 concentration, and vector genome copy number. Serum samples were also analyzed for IL-10 concentration and vector genome copy number. Synovial membrane was collected on day 84. Synovial fluid IL-10 was significantly increased within 48 h of AAV5-IL-10 injection and remained increased, compared to PBS-injected joints, until day 84. Serum IL-10 was not different between groups. Vector administration did not cause a significant synovial inflammatory response. Vector genomes were detectable in the plasma, synovial fluid, and synovial membrane of AAV5-IL-10-injected horses only. IL-10 has the potential to modulate the articular inflammatory response, thereby protecting cartilage from degradation and osteoarthritis. This study demonstrates the feasibility and efficiency of intra-articular AAV5-IL-10, and future studies investigating the chondroprotective effects of IL-10 in inflamed joints are warranted.
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Publication Date: 2019-12-18 PubMed ID: 31773987PubMed Central: PMC7872004DOI: 10.1089/hum.2019.195Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

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 tries to ascertain the potential of gene therapy in managing joint inflammation through intra-articular administration of an anti-inflammatory cytokine, Interleukin-10 (IL-10). It demonstrates that this method provides sustained release of IL-10, controlling inflammation without triggering systemic effects or local inflammation in horse subjects.

Research Context

  • Post-traumatic inflammation caused by joint trauma can lead to severe consequences such as irreversible post-traumatic osteoarthritis if the responses of inflammatory cytokines and degradative enzymes are intense.
  • The cytokine, Interleukin-10 (IL-10) is noted for its potent anti-inflammatory effects and ‘chondroprotective’ properties – that is, it is capable of shield the cartilage.
  • The researchers propose using gene therapy, specifically an AAV5 vector aiding the overexpression of IL-10, as a strategic method to deliver high, prolonged doses of IL-10 to affected joints.

Methods and Hypotheses

  • The scientists hypothesized that using the AAV5 vector would stimulate immediate and persistent IL-10 expression following intra-articular injection, which would not affect systemic circulation or instigate a local inflammatory response.
  • To affirm these theories, researchers divided twelve horses into a treatment group and a control group, injecting 10 vector genomes/joint or phosphate-buffered saline (PBS) into the middle carpal joints of horses respectively.
  • Samples of synovial fluid were taken periodically and analysed to monitor IL-10 concentration, inflammatory changes, and vector genome copy number. Serum samples were similarly analysed for IL-10 concentration and vector genome.

Findings and Conclusions

  • The findings confirm that IL-10 in synovial fluid dramatically increased within 48 hours of AAV5-IL-10 injection and maintained this high level until day 84 when compared with PBS-injected joints.
  • There were no significant differences in the serum IL-10 levels between both groups, nor any notable synovial inflammatory response caused by vector administration.
  • The vector genomes could only be identified in the plasma, synovial fluid, and synovial membrane of horses injected with the AAV5-IL-10.
  • These findings underscore the potential of IL-10 as a modulator of the articular inflammatory response, thus protecting cartilage from degradation and osteoarthritis.
  • This research successfully highlights the feasibility and effectiveness of the intra-articular AAV5-IL-10 method, and encourages further research into the chondroprotective effects of IL-10 in inflamed joints.

Cite This Article

APA
Moss KL, Jiang Z, Dodson ME, Linardi RL, Haughan J, Gale AL, Grzybowski C, Engiles JE, Stefanovski D, Robinson MA, Ortved KF. (2019). Sustained Interleukin-10 Transgene Expression Following Intra-Articular AAV5-IL-10 Administration to Horses. Hum Gene Ther, 31(1-2), 110-118. https://doi.org/10.1089/hum.2019.195

Publication

Human gene therapy
ISSN: 1557-7422
NlmUniqueID: 9008950
Country: United States
Language: English
Volume: 31
Issue: 1-2
Pages: 110-118

Researcher Affiliations

Moss, Kaitlyn L
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, Pennsylvania.
Jiang, Zibin
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, Pennsylvania.
Dodson, Michael E
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, Pennsylvania.
Linardi, Renata L
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, Pennsylvania.
Haughan, Joanne
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, Pennsylvania.
Gale, Alexis L
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, Pennsylvania.
Grzybowski, Cara
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, Pennsylvania.
Engiles, Julie E
  • Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania.
Stefanovski, Darko
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, Pennsylvania.
Robinson, Mary A
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, Pennsylvania.
  • Pennsylvania Equine Toxicology & Research Center, West Chester University, West Chester, Pennsylvania.
Ortved, Kyla F
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, Pennsylvania.

MeSH Terms

  • Animals
  • Biomarkers
  • Cytokines / metabolism
  • Dependovirus
  • Disease Models, Animal
  • Gene Expression
  • Genetic Therapy / methods
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Genome, Viral
  • Horses
  • Humans
  • Immunohistochemistry
  • Inflammation Mediators / metabolism
  • Injections, Intra-Articular
  • Interleukin-10 / genetics
  • Osteoarthritis / genetics
  • Osteoarthritis / pathology
  • Osteoarthritis / therapy
  • Parvovirinae / genetics
  • Synovial Fluid / metabolism
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology
  • Transgenes

Grant Funding

  • T35 OD010919 / NIH HHS

Conflict of Interest Statement

No competing financial interests exist for any of the authors.

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