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Human gene therapy. Clinical development2018; 29(2); 101-112; doi: 10.1089/humc.2017.143

Self-Complementary Adeno-Associated Virus-Mediated Interleukin-1 Receptor Antagonist Gene Delivery for the Treatment of Osteoarthritis: Test of Efficacy in an Equine Model.

Abstract: The authors are investigating self-complementary adeno-associated virus (scAAV) as a vector for intra-articular gene-delivery of interleukin-1 receptor antagonist (IL-1Ra), and its therapeutic capacity in the treatment of osteoarthritis (OA). To model gene transfer on a scale proportional to the human knee, a frequent site of OA incidence, studies were focused on the joints of the equine forelimb. Using AAV2.5 capsid and equine IL-1Ra as a homologous transgene, a functional ceiling dose of ∼5 × 10 viral genomes was previously identified, which elevated the steady state levels of eqIL-1Ra in synovial fluids by >40-fold over endogenous production for at least 6 months. Here, using an osteochondral fragmentation model of early OA, the functional capacity of scAAV.IL-1Ra gene-delivery was examined in equine joints over a period of 12 weeks. In the disease model, transgenic eqIL-1Ra expression was several fold higher than seen previously in healthy joints, and correlated directly with the severity of joint pathology at the time of treatment. Despite wide variation in expression, the steady-state eqIL-1Ra in synovial fluids exceeded that of IL-1 by >400-fold in all animals, and a consistent treatment effect was observed. This included a 30-40% reduction in lameness and ∼25% improvement in total joint pathology by both magnetic resonance imaging and arthroscopic assessments, which included reduced joint effusion and synovitis, and improved repair of the osteochondral lesion. No vector-related increase in eqIL-1Ra levels in blood or urine was noted. Cumulatively, these studies in the equine model indicate scAAV.IL-1Ra administration is reasonably safe and capable of sustained therapeutic IL-1Ra production intra-articularly in joints of human scale. This profile supports consideration for human testing in OA.
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Publication Date: 2018-06-06 PubMed ID: 29869535PubMed Central: PMC6007806DOI: 10.1089/humc.2017.143Google Scholar: Lookup
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  • Research Support
  • N.I.H.
  • Extramural

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 details experiments that used self-complementary adeno-associated virus (scAAV) as a vehicle to introduce interleukin-1 receptor antagonist (IL-1Ra) genes into horse’s bodies for the sake of treating osteoarthritis (OA).

Experimental Procedure

  • The researchers used AAV2.5 capsid and equine IL-1Ra, similar to human IL-1Ra, as a transgene to conduct this study.
  • To conduct the study on a scale similar to human joints, they focused on the joints of horse’s forelimbs.
  • Earlier studies had shown that a functional dose of about 5 x 10 viral genomes elevated the levels of equine IL-1Ra production by over 40 times for at least 6 months.
  • In this study, the researchers sought to validate the efficacy of gene-delivery using scAAV.IL-1Ra over a period of 12 weeks, using an osteochondral fragmentation model of early OA.

Results and Observations

  • Within the disease model, the expression of transgenic eqIL-1Ra was found to be much higher than previously observed in healthy joints, and the expression level directly correlated with the severity of joint pathology at the time of treatment.
  • No matter the variance in expression, eqIL-1Ra levels in synovial fluids were observed to be greater than IL-1 by over 400 times in all animals.
  • More specifically, a consistent treatment effect included a 30-40% decrease in lameness and approximately a 25% improvement in total joint pathology. This was observed through MRIs and arthroscopic assessments, which noted less joint effusion and synovitis, and improved repair of the osteochondral lesion.
  • No increase in eqIL-1Ra levels within the blood or urine was noted that could be traced back to the vector.

Conclusions

  • Overall, the trials conducted in the equine model indicated that scAAV.IL-1Ra administration was relatively safe and effective at sustainably producing therapeutic IL-1Ra intra-articularly in joints the size of human ones.
  • These results suggest scAAV.IL-1Ra could be considered for human trials in treating OA.

Cite This Article

APA
Watson Levings RS, Smith AD, Broome TA, Rice BL, Gibbs EP, Myara DA, Hyddmark EV, Nasri E, Zarezadeh A, Levings PP, Lu Y, White ME, Dacanay EA, Foremny GB, Evans CH, Morton AJ, Winter M, Dark MJ, Nickerson DM, Colahan PT, Ghivizzani SC. (2018). Self-Complementary Adeno-Associated Virus-Mediated Interleukin-1 Receptor Antagonist Gene Delivery for the Treatment of Osteoarthritis: Test of Efficacy in an Equine Model. Hum Gene Ther Clin Dev, 29(2), 101-112. https://doi.org/10.1089/humc.2017.143

Publication

Human gene therapy. Clinical development
ISSN: 2324-8645
NlmUniqueID: 101607433
Country: United States
Language: English
Volume: 29
Issue: 2
Pages: 101-112

Researcher Affiliations

Watson Levings, Rachael S
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Smith, Andrew D
  • 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Broome, Ted A
  • 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Rice, Brett L
  • 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Gibbs, Eric P
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Myara, David A
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Hyddmark, E Viktoria
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Nasri, Elham
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Zarezadeh, Ali
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Levings, Padraic P
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Lu, Yuan
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
White, Margaret E
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Dacanay, E Anthony
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Foremny, Gregory B
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.
Evans, Christopher H
  • 3 Rehabilitation Medicine Research Center, Mayo Clinic , Rochester, Minnesota.
Morton, Alison J
  • 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Winter, Mathew
  • 4 Department of Small Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Dark, Michael J
  • 5 Department of Infectious Diseases and Pathology, University of Florida , Gainesville, Florida.
Nickerson, David M
  • 6 Department of Statistics and Actuarial Science, University of Florida , Gainesville, Florida.
Colahan, Patrick T
  • 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida.
Ghivizzani, Steven C
  • 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida.

MeSH Terms

  • Animals
  • Dependovirus / genetics
  • Disease Models, Animal
  • Gene Transfer Techniques / adverse effects
  • Genetic Therapy
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / adverse effects
  • Genetic Vectors / genetics
  • Horses
  • Humans
  • Injections, Intra-Articular
  • Interleukin 1 Receptor Antagonist Protein / administration & dosage
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Knee / pathology
  • Osteoarthritis / genetics
  • Osteoarthritis / pathology
  • Osteoarthritis / therapy

Conflict of Interest Statement

C.H.E. and S.C.G. are inventors on several patents and patent applications describing cell- and gene-based therapies for arthritis and connective tissue disorders.

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