IL-1ra gene therapy in equine osteoarthritis improves physiological, anatomical, and biological outcomes of joint degeneration

Laurie R. Goodrich Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO

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 DVM, PhD
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C. Wayne McIlwraith Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO

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 BVSc, PhD, DSc
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Josh Grieger UNC Gene Therapy Center, University of North Carolina, Chapel Hill, NC

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 PhD
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Virginia Byers Kraus Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC
Division of Rheumatology, Duke University School of Medicine, Durham, NC

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 MD, PhD
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Thomas Stabler Division of Rheumatology, Duke University School of Medicine, Durham, NC

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Natasha Werpy Equine Diagnostic Imaging Inc, Archer, FL

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Jennifer Phillips Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO

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R. Jude Samulski UNC Gene Therapy Center, University of North Carolina, Chapel Hill, NC

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David Frisbie Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO

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 DVM, PhD

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Abstract

OBJECTIVE

To evaluate the effects of a gene transfer approach to IL-1β inhibition in an equine osteochondral chip fragment model of joint injury using a self-complementary adeno-associated virus with interleukin receptor antagonist transgene cassette (scAAVIL-1ra), as posttraumatic osteoarthritis in horses, similar to people, is a significant clinical problem.

ANIMALS

16 horses were utilized for the study.

METHODS

All horses had an osteochondral chip fragment induced arthroscopically in one middle carpal joint while the contralateral joint was sham operated. Eight horses received either scAAVIL-1ra or saline in the osteoarthritis joint. Horses were evaluated over 70 days clinically (lameness, imaging, and biomarker analysis) and euthanized at 70 days and evaluated grossly, with imaging and histopathology.

RESULTS

The following findings were statistically significant. Injection of scAAVIL-1ra resulted in high synovial fluid levels of IL-1ra (0.5 to 9 μg/mL) throughout the duration of the experiment (70 days). Over the duration, we observed scAAVIL-1ra to improve lameness (lameness score relative improvement of 1.2 on a scale of 0 to 5), cause suppression of prostaglandin E2 (a relative decline of 30 pg/mL), and result in histological improvement in articular cartilage (decreased chondrocyte loss and chondrone formation) and subchondral bone (less osteochondral splitting and osteochondral lesions). Within the synovial membrane of scAAVIL-1ra–treated joints, we also observed perivascular infiltration with CD3-positive WBCs, suggesting lymphocytic T-cell perivascular infiltration commonly observed with viral transduction.

CLINICAL RELEVANCE

These data provide support for further evaluation and optimization of scAAVIL-1ra gene therapy to treat equine osteoarthritis.

Abstract

OBJECTIVE

To evaluate the effects of a gene transfer approach to IL-1β inhibition in an equine osteochondral chip fragment model of joint injury using a self-complementary adeno-associated virus with interleukin receptor antagonist transgene cassette (scAAVIL-1ra), as posttraumatic osteoarthritis in horses, similar to people, is a significant clinical problem.

ANIMALS

16 horses were utilized for the study.

METHODS

All horses had an osteochondral chip fragment induced arthroscopically in one middle carpal joint while the contralateral joint was sham operated. Eight horses received either scAAVIL-1ra or saline in the osteoarthritis joint. Horses were evaluated over 70 days clinically (lameness, imaging, and biomarker analysis) and euthanized at 70 days and evaluated grossly, with imaging and histopathology.

RESULTS

The following findings were statistically significant. Injection of scAAVIL-1ra resulted in high synovial fluid levels of IL-1ra (0.5 to 9 μg/mL) throughout the duration of the experiment (70 days). Over the duration, we observed scAAVIL-1ra to improve lameness (lameness score relative improvement of 1.2 on a scale of 0 to 5), cause suppression of prostaglandin E2 (a relative decline of 30 pg/mL), and result in histological improvement in articular cartilage (decreased chondrocyte loss and chondrone formation) and subchondral bone (less osteochondral splitting and osteochondral lesions). Within the synovial membrane of scAAVIL-1ra–treated joints, we also observed perivascular infiltration with CD3-positive WBCs, suggesting lymphocytic T-cell perivascular infiltration commonly observed with viral transduction.

CLINICAL RELEVANCE

These data provide support for further evaluation and optimization of scAAVIL-1ra gene therapy to treat equine osteoarthritis.

Supplementary Materials

    • Supplementary Figure S1 (PDF 300 KB)
    • Supplementary Figure S2 (PDF 837 KB)
    • Supplementary Figure S3 (PDF 257 KB)
    • Supplementary Table S1 (PDF 203 KB)
    • Supplementary Table S2 (PDF 216 KB)
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