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Gene therapy2023; doi: 10.1038/s41434-023-00420-2

A pilot study to determine the optimal dose of scAAVIL-1ra in a large animal model of post-traumatic osteoarthritis.

Abstract: Gene therapy approaches using adeno-associated viral vectors have been successfully tested in the equine post-traumatic osteoarthritis (PTOA) model. Owing to differences in the levels of transgene expression and adverse tissue reactions observed in published studies, we sought to identify a safe therapeutic dose of scAAVIL-1ra in an inflamed and injured joint that would result in improved functional outcomes without any adverse events. scAAVIL-1ra was delivered intra-articularly over a 100-fold range, and horses were evaluated throughout and at the end of the 10-week study. A dose-related increase in IL-1ra levels with a decrease in PGE levels was observed, with the peak IL-1ra concentration being observed 7 days post-treatment in all groups. Perivascular infiltration with mononuclear cells was observed within the synovial membrane of the joint treated with the highest viral dose of 5 × 10 vg, but this was absent in the lower-dosed joints. The second-highest dose of scAAVeqIL-1ra 5 × 10 vg demonstrated elevated IL-1ra levels without any cellular response in the synovium. Taken together, the data suggest that the 10-fold lower dose of 5 × 10vg scAAVIL-1ra would be a safe therapeutic dose in an equine model of PTOA.
© 2023. The Author(s).
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Publication Date: 2023-09-11 PubMed ID: 37696981PubMed Central: 3626203DOI: 10.1038/s41434-023-00420-2Google 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 investigates the use of gene therapy to treat post-traumatic osteoarthritis in horses. The researchers aim to identify a safe dosage of a specific gene therapy treatment that results in improved outcomes without causing any adverse reactions.

Summary of Research Methodology

  • The researchers used an adeno-associated viral vectors gene therapy approach which has previously been successful in treating post-traumatic osteoarthritis (PTOA) in equine models.
  • The specific treatment, known as scAAVIL-1ra, was delivered intra-articularly, or within the joint, over a 100-fold range.
  • Horses were evaluated at intervals and at the end of a 10-week study period to determine the effects of varying dosages of the treatment.

Results of the Study

  • The study findings indicated a dose-related increase in IL-1ra levels. This type of protein is directly related to anti-inflammation. With a decrease in PGE levels, which are associated with inflammation in traumatic injuries, it is inferred that the treatment has potential anti-inflammatory effects.
  • Peak IL-1ra concentration was observed 7 days following treatment in all groups, suggesting that this could be the optimal time for measuring results.
  • However, an adverse tissue reaction was observed in the form of perivascular infiltration with mononuclear cells, specifically in the synovial membrane of the joint treated with the highest viral dose (5 × 10 vg).
  • This adverse reaction was not observed in joints treated with lower doses.

Conclusion

  • The second-highest dose of 5 × 10 vg demonstrated elevated IL-1ra levels without provoking any adverse cellular reaction in the synovium, suggesting that it might be a more appropriate dosage.
  • Overall, the data suggest a therapeutic dose 10-fold lower than the highest dose investigated (5 × 10vg) would be safe for use in an equine model of PTOA.
  • This research opens a door to further explore the potential of gene therapy in managing and treating osteoarthritis in large animals such as horses.

Cite This Article

APA
Thampi P, Seabaugh KA, Pezzanite LM, Chu CR, Phillips JN, Grieger JC, McIlwraith CW, Samulski RJ, Goodrich LR. (2023). A pilot study to determine the optimal dose of scAAVIL-1ra in a large animal model of post-traumatic osteoarthritis. Gene Ther. https://doi.org/10.1038/s41434-023-00420-2

Publication

Gene therapy
ISSN: 1476-5462
NlmUniqueID: 9421525
Country: England
Language: English

Researcher Affiliations

Thampi, P
  • Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Colorado State University, Fort Collins, CO, USA.
Seabaugh, K A
  • Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Colorado State University, Fort Collins, CO, USA.
Pezzanite, L M
  • Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Colorado State University, Fort Collins, CO, USA.
Chu, C R
  • Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.
  • Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA.
Phillips, J N
  • Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Colorado State University, Fort Collins, CO, USA.
Grieger, J C
  • Gene Therapy Center, University of North Carolina, Chapel Hill, NC, USA.
McIlwraith, C W
  • Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Colorado State University, Fort Collins, CO, USA.
Samulski, R J
  • Gene Therapy Center, University of North Carolina, Chapel Hill, NC, USA.
Goodrich, L R
  • Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Colorado State University, Fort Collins, CO, USA. laurie.goodrich@colostate.edu.

Grant Funding

  • 62326995-156499 / U.S. Department of Defense (United States Department of Defense)
  • W81XWH1810572 / U.S. Department of Defense (United States Department of Defense)
  • W81XWH1810572 / U.S. Department of Defense (United States Department of Defense)
  • 62326995-156499 / U.S. Department of Defense (United States Department of Defense)
  • W81XWH1810572 / U.S. Department of Defense (United States Department of Defense)
  • 62326995-156499 / U.S. Department of Defense (United States Department of Defense)
  • W81XWH1810572 / U.S. Department of Defense (United States Department of Defense)
  • W81XWH1810572 / U.S. Department of Defense (United States Department of Defense)
  • W81XWH1810572 / U.S. Department of Defense (United States Department of Defense)
  • 62326995-156499 / U.S. Department of Defense (United States Department of Defense)
  • W81XWH1810572 / U.S. Department of Defense (United States Department of Defense)

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Citations

This article has been cited 3 times.
  1. Kearney CM, Korthagen NM, Plomp SGM, Labberté MC, de Grauw JC, van Weeren PR, Brama PAJ. A Translational Model for Repeated Episodes of Joint Inflammation: Welfare, Clinical and Synovial Fluid Biomarker Assessment. Animals (Basel) 2023 Oct 12;13(20).
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  2. Walton BL, Shattuck-Brandt R, Hamann CA, Tung VW, Colazo JM, Brand DD, Hasty KA, Duvall CL, Brunger JM. A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine. Osteoarthritis Cartilage 2025 Feb;33(2):231-240.
    doi: 10.1016/j.joca.2024.12.002pubmed: 39706287google scholar: lookup
  3. Walton BL, Shattuck-Brandt R, Hamann CA, Tung VW, Colazo JM, Brand DD, Hasty KA, Duvall CL, Brunger JM. A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine. bioRxiv 2024 Feb 15;.
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