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Home / Equine Research Bank / Gene Ther / scAAVIL-1ra dosing trial in a large animal model and validat...
Gene therapy2015; 22(7); 536-545; doi: 10.1038/gt.2015.21

scAAVIL-1ra dosing trial in a large animal model and validation of long-term expression with repeat administration for osteoarthritis therapy.

Abstract: A gene therapeutic approach to treat osteoarthritis (OA) appears to be on the horizon for millions of people who suffer from this disease. Previously we described optimization of a scAAVIL-1ra gene therapeutic vector and initially tested this in an equine model verifying long-term intrasynovial IL-1ra protein at therapeutic levels. Using this vector, we carried out a dosing trial in six horses to verify protein levels and establish a dose that would express relevant levels of therapeutic protein for extended periods of time (8 months). A novel arthroscopic procedure used to detect green fluorescence protein (GFP) fluorescence intrasynovially confirmed successful transduction of the scAAVGFP vector in both the synovial and cartilage tissues. No evidence of intra-articular toxicity was detected. Immune responses to vector revealed development of neutralizing antibodies (Nabs) within 2 weeks of administration, which persisted for the duration of the study but did not lower protein expression intra-articularly. Re-dosing with a different serotype to attain therapeutic levels of protein confirmed establishment of successful transduction. This is the first study in an equine model to establish a dosing/redosing protocol, as well as examine the Nab response to capsid and supports further clinical investigation to determine the clinical efficacy of scAAVIL-1ra to treat OA.
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Publication Date: 2015-04-23 PubMed ID: 25902762PubMed Central: PMC5567794DOI: 10.1038/gt.2015.21Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural
  • Research Support
  • Non-U.S. Gov't

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 study investigated a new gene therapeutic approach to treat osteoarthritis using a therapeutic vector, scAAVIL-1ra, with testing done on horses to monitor therapeutic protein levels over an 8-month period.

Study design and Methodology

  • The researchers created a gene therapeutic vector, scAAVIL-1ra, designed to produce therapeutic levels of anti-inflammatory protein, IL-1ra, directly in the joint. This protein can help treat osteoarthritis by reducing inflammation.
  • The vector was tested on six horses, where the team carried out a dosing trial over an extended period of eight months to monitor the levels of the therapeutic protein produced.

Experimental Procedure

  • A novel arthroscopic procedure was used to detect green fluorescence protein (GFP) fluorescence within the joint. This helped confirm successful transduction of the scAAVGFP vector in both the synovial and cartilage tissues.
  • No signs of toxicity from the procedure were detected in the joint.

Immune Response and Redosing

  • The study also noted the development of neutralizing antibodies (Nabs) within two weeks of administration. These antibodies persisted throughout the study but did not decrease intra-articular protein expression.
  • The researchers followed up with a second dosage using a different serotype. This was to achieve therapeutic levels of protein, thereby confirming the successful establishment of transduction.

Significance and Implications

  • This study is the first of its kind in an equine model to establish a dosing and re-dosing protocol and to examine the Nab response to capsid.
  • The findings suggest the potential of the scAAVIL-1ra gene therapy to treat osteoarthritis, paving the way for further clinical investigations.

Cite This Article

APA
Goodrich LR, Grieger JC, Phillips JN, Khan N, Gray SJ, McIlwraith CW, Samulski RJ. (2015). scAAVIL-1ra dosing trial in a large animal model and validation of long-term expression with repeat administration for osteoarthritis therapy. Gene Ther, 22(7), 536-545. https://doi.org/10.1038/gt.2015.21

Publication

Gene therapy
ISSN: 1476-5462
NlmUniqueID: 9421525
Country: England
Language: English
Volume: 22
Issue: 7
Pages: 536-545

Researcher Affiliations

Goodrich, L R
  • Orthopaedic Research Center, Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, USA.
Grieger, J C
  • UNC Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Phillips, J N
  • Orthopaedic Research Center, Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, USA.
Khan, N
  • UNC Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Gray, S J
  • UNC Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
McIlwraith, C W
  • Orthopaedic Research Center, Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, USA.
Samulski, R J
  • UNC Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

MeSH Terms

  • Animals
  • Antibodies, Neutralizing / metabolism
  • Carpal Joints / immunology
  • Carpal Joints / metabolism
  • Carpal Joints / pathology
  • Cartilage, Articular / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Immunologic
  • Gene Expression / immunology
  • Genetic Therapy
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / immunology
  • Genetic Vectors / therapeutic use
  • Horses
  • Interleukin 1 Receptor Antagonist Protein / immunology
  • Interleukin 1 Receptor Antagonist Protein / metabolism
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Osteoarthritis / genetics
  • Osteoarthritis / immunology
  • Osteoarthritis / metabolism
  • Osteoarthritis / therapy
  • Synovial Membrane / metabolism

Grant Funding

  • K08 AR054903 / NIAMS NIH HHS
  • R01 AI072176 / NIAID NIH HHS
  • R01AI072176 / NIAID NIH HHS
  • R01AR064369 / NIAMS NIH HHS
  • 1K08AR054903-01A2 / NIAMS NIH HHS
  • P01HL112761 / NHLBI NIH HHS
  • R01 AR064369 / NIAMS NIH HHS
  • R25 GM089569 / NIGMS NIH HHS
  • P01 HL112761 / NHLBI NIH HHS

Conflict of Interest Statement

. The authors declare no conflict of interest.

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Citations

This article has been cited 21 times.
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