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Molecular therapy. Nucleic acids2013; 2(2); e70; doi: 10.1038/mtna.2012.61

Optimization of scAAVIL-1ra In Vitro and In Vivo to Deliver High Levels of Therapeutic Protein for Treatment of Osteoarthritis.

Abstract: Osteoarthritis (OA) affects over 40 million people annually. We evaluated interleukin-1 receptor antagonist (IL-1ra) gene transfer in an equine model based on IL-1ra protein therapy which inhibits inflammation through blocking IL-1. Using the self-complementary adeno-associated virus (scAAV)IL-1ra equine gene as a starting construct, we optimized the transgene cassette by analyzing promoters (cytomegalovirus (CMV) versus chicken β-actin hybrid (CBh)), coding sequences (optimized versus unoptimized), vector capsid (serotype 2 versus chimeric capsid), and biological activity in vitro. AAV serotypes 2 and 2.5 CMV scAAVoptIL-1ra were tested in equine joints. We evaluated two doses of scAAVIL-1ra, scAAVGFP, and saline. We developed a novel endoscopy procedure and confirmed vector-derived transgene expression (GFP) in chondrocytes 6 months post-injection. AAVIL-1ra therapeutic protein levels were 200-800 ng/ml of synovial fluid over 23 and 186 days, respectively. No evidence of intra-articular toxicity was detected and no vector genomes were found in contralateral joints based on GFP fluorescence microscopy and quantitative PCR. Finally, we assayed vector-derived IL-1ra activity based on functional assays which supported anti-inflammatory activity of our protein. These studies represent the first large animal intra-articular gene transfer approach with a therapeutic gene using scAAV and demonstrate high levels of protein production over extended time supporting further clinical investigation using scAAV gene therapy for OA.Molecular Therapy - Nucleic Acids (2013) 2, e70; doi:10.1038/mtna.2012.61; published online 5 February 2013.
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Publication Date: 2013-02-05 PubMed ID: 23385523PubMed Central: PMC3586798DOI: 10.1038/mtna.2012.61Google 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 research article discusses an experiment done to optimize a model using a gene linked to treatment strategies for Osteoarthritis (OA). Based on interleukin-1 receptor antagonist (IL-1ra) protein therapy, the researchers used an equine model for gene transfer and tested different factors for effective delivery of high levels of therapeutic protein. The results showed no toxicity within joint areas and high protein production over an extended period.

Objective of the Research

  • The primary goal of this research was to optimize a gene transfer model based on a specific protein therapy (IL-1ra) for alleviating inflammation related to Osteoarthritis (OA). The optimization process involved evaluating and testing various elements such as the promoters, coding sequences, vector capsid, and biological activity of the gene.

Methodology

  • The transgene cassette was optimized by comparing promoters (cytomegalovirus (CMV) versus chicken β-actin hybrid (CBh)), coding sequences (optimized versus unoptimized), and vector capsid (serotype 2 versus chimeric capsid).
  • The researchers subsequently conducted biological activity tests of the gene in vitro.
  • The researchers introduced the selected gene with optimized elements into equine joints and assessed the outcome for two different doses compared against a control group.
  • Finally, a novel endoscopy procedure was developed to confirm the expression of the injected gene in chondrocytes, the cells that make up cartilage, over six months post-injection.

Results and Findings

  • The protein molecules produced from the gene transfer were found in high levels (200-800 ng/ml) in synovial fluid, the lubricating liquid in joints, over an extended time (between 23 and 186 days post-injection).
  • No evidence of toxicity within the joint areas was detected, a vital factor considering the critical function of joints and the potential adverse effects that could arise from it.
  • In addition, no vector genomes were found in contralateral joints, suggesting that the gene transfer was localized and did not spread unnecessarily to other joint areas.
  • The presence of IL-1ra activity was confirmed through functional assays, proving that the therapeutic protein produced did possess anti-inflammatory activity.

Significance and Conclusions

  • This research represents one of the first advances in large-animal intra-articular gene transfer approaches using a therapeutic gene.
  • The study’s findings are promising and demonstrate high levels of protein production over extended periods, making it a possible solution for therapy in treating OA.
  • However, further investigation and clinical studies using this gene therapy technique for Osteoarthritis are required to validate and strengthen the research findings.

Cite This Article

APA
Goodrich LR, Phillips JN, McIlwraith CW, Foti SB, Grieger JC, Gray SJ, Samulski RJ. (2013). Optimization of scAAVIL-1ra In Vitro and In Vivo to Deliver High Levels of Therapeutic Protein for Treatment of Osteoarthritis. Mol Ther Nucleic Acids, 2(2), e70. https://doi.org/10.1038/mtna.2012.61

Publication

Molecular therapy. Nucleic acids
ISSN: 2162-2531
NlmUniqueID: 101581621
Country: United States
Language: English
Volume: 2
Issue: 2
Pages: e70

Researcher Affiliations

Goodrich, Laurie R
  • Orthopaedic Research Center, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado, USA.
Phillips, Jennifer N
    McIlwraith, C Wayne
      Foti, Stacey B
        Grieger, Joshua C
          Gray, Steven J
            Samulski, R Jude

              Grant Funding

              • K08 AR054903 / NIAMS NIH HHS
              • R01 AI072176 / NIAID NIH HHS
              • U54 AR056953 / NIAMS NIH HHS

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              This article has been cited 24 times.
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