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Human gene therapy2015; 26(3); 161-171; doi: 10.1089/hum.2014.050

Humoral and cell-mediated immune response, and growth factor synthesis after direct intraarticular injection of rAAV2-IGF-I and rAAV5-IGF-I in the equine middle carpal joint.

Abstract: Intraarticular (IA) administration of viral vectors expressing a therapeutic transgene is an attractive treatment modality for osteoarthritis (OA) as the joint can be treated as a contained unit. Humoral and cell-mediated immune responses in vivo can limit vector effectiveness. Transduction of articular tissues has been investigated; however, the immune response to IA vectors remains largely unknown. We hypothesized that IA rAAV2 and rAAV5 overexpressing insulin-like growth factor-I (IGF-I) would result in long-term IGF-I formation but would also induce neutralizing antibodies (NAb) and anti-capsid effector T cells. Twelve healthy horses were assigned to treatment (rAAV2 or rAAV5) or control (saline) groups. Middle carpal joints were injected with 5×10(11) vector genomes/joint. Synovial fluid was analyzed for changes in composition, NAb titers, immunoglobulin isotypes, proinflammatory cytokines, and IGF-I. Serum was analyzed for antibody titers and cytokines. A T cell restimulation assay was used to assess T cell responses. Injection of rAAV2- or rAAV5-IGF-I did not induce greater inflammation compared with saline. Synovial fluid IGF-I was significantly increased in both rAAV2- and rAAV5-IGF-I joints by day 14 and remained elevated until day 56; however, rAAV5 achieved the highest concentrations. A capsid-specific T cell response was not noted although all virus-treated horses had increased NAbs in serum and synovial fluid after treatment. Taken together, our data show that IA injection of rAAV2- or rAAV5-IGF-I does not incite a clinically detectable inflammatory or cell-mediated immune response and that IA gene therapy using minimally immunogenic vectors represents a clinically relevant tool for treating articular disorders including OA.
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Publication Date: 2015-02-24 PubMed ID: 25705927PubMed Central: PMC4367237DOI: 10.1089/hum.2014.050Google 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.

The research paper discusses an examination of the immune system’s response and growth factor synthesis following direct intra-articular injection of Recombinant Adeno-Associated Virus 2 and 5 (rAAV2 and rAAV5) with insulin-like growth factor-I (IGF-I) into horses’ middle carpal joint. The findings suggest that this technique does not cause significant inflammation or immune response, making it a potentially viable innovative treatment for articular disorders including osteoarthritis (OA).

Objective and Methodology

  • The researchers hypothesized that a direct joint injection of rAAV2 and rAAV5 carrying the IGF-I gene would stimulate the production of IGF-I, a growth factor beneficial for joint health. They were also investigating whether this process would trigger an immune response that could limit the therapy’s effectiveness.
  • The study utilized twelve healthy horses assigned to either treatment groups or control groups. Treatment consisted of IA injections of either rAAV2-IGF-I or rAAV5-IGF-I, while the control group received saline.
  • Over time, the researchers analyzed synovial fluid for alterations in composition, neutralizing antibodies titers, immunoglobulin isotypes, pro-inflammatory cytokines, and IGF-I levels. They also scrutinized serum for antibody titers and cytokines. A T cell restimulation assay was used to measure T cell responses.

Findings

  • The result showed no significant inflammation after injection of either rAAV2 or rAAV5. It was observed that the IGF-I content in the synovial fluid increased markedly in both rAAV2 and rAAV5 injected joints by day 14 after injection and remained higher until day 56.
  • The rAAV5 treatment group achieved the highest concentrations of IGF-I. All horses treated with the virus indicated an increase in neutralizing antibodies in serum and synovial fluid after the treatment was administered.
  • Interestingly, the experiment did not identify an increase in T cell responses, despite the rise in neutralizing antibodies.

Conclusion

  • Based on the findings, the research concludes that IA gene therapies using minimally immunogenic vectors such as rAAV2 or rAAV5 do not invoke a damaging immune response or clinically significant inflammation.
  • This makes them potentially useful tools in the treatment of articular disorders, including osteoarthritis.

Cite This Article

APA
Ortved K, Wagner B, Calcedo R, Wilson J, Schaefer D, Nixon A. (2015). Humoral and cell-mediated immune response, and growth factor synthesis after direct intraarticular injection of rAAV2-IGF-I and rAAV5-IGF-I in the equine middle carpal joint. Hum Gene Ther, 26(3), 161-171. https://doi.org/10.1089/hum.2014.050

Publication

Human gene therapy
ISSN: 1557-7422
NlmUniqueID: 9008950
Country: United States
Language: English
Volume: 26
Issue: 3
Pages: 161-171

Researcher Affiliations

Ortved, Kyla
  • 1 Department of Clinical Sciences, Cornell University College of Veterinary Medicine , Ithaca, NY 14853.
Wagner, Bettina
    Calcedo, Roberto
      Wilson, James
        Schaefer, Deanna
          Nixon, Alan

            MeSH Terms

            • Animals
            • Antibodies, Neutralizing / immunology
            • Carpal Joints / immunology
            • Dependovirus
            • Genetic Vectors / administration & dosage
            • Genetic Vectors / pharmacology
            • Horses
            • Immunity, Cellular / drug effects
            • Immunity, Humoral / drug effects
            • Immunoglobulin Isotypes / immunology
            • Injections, Intra-Articular
            • Insulin-Like Growth Factor I / pharmacology
            • Intercellular Signaling Peptides and Proteins / biosynthesis
            • Real-Time Polymerase Chain Reaction
            • Spectrophotometry, Ultraviolet
            • Statistics, Nonparametric
            • Synovial Membrane / chemistry

            Grant Funding

            • 5R01-AR055373 / NIAMS NIH HHS
            • P30-DK047757 / NIDDK NIH HHS

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            Citations

            This article has been cited 7 times.
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