Sustained Interleukin-10 Transgene Expression Following Intra-Articular AAV5-IL-10 Administration to Horses
| Autor: | Kaitlyn L. Moss, Cara Grzybowski, Michael E. Dodson, Mary A. Robinson, Julie E. Engiles, Kyla F. Ortved, Joanne Haughan, Alexis L. Gale, Zibin Jiang, Renata L. Linardi, Darko Stefanovski |
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| Rok vydání: | 2020 |
| Předmět: |
Transgene
Genetic enhancement Genetic Vectors Gene Expression Arthritis Inflammation Genome Viral Osteoarthritis Injections Intra-Articular Proinflammatory cytokine 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Parvovirinae Synovial Fluid Genetics medicine Animals Humans Horses Transgenes Molecular Biology Research Articles 030304 developmental biology 0303 health sciences business.industry Synovial Membrane food and beverages Genetic Therapy Dependovirus medicine.disease Immunohistochemistry Interleukin-10 Disease Models Animal Interleukin 10 030220 oncology & carcinogenesis Immunology Cytokines Molecular Medicine Inflammation Mediators medicine.symptom business Biomarkers |
| Zdroj: | Hum Gene Ther |
| ISSN: | 1557-7422 1043-0342 |
| Popis: | 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(12) 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 in vivo are warranted. |
| Databáze: | OpenAIRE |
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