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

L. R. Goodrich, J. C. Grieger, J. N. Phillips, N. Khan, S. J. Gray, C. W. McIlwraith, R. J. Samulski

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)536-545
Number of pages10
JournalGene Therapy
Volume22
Issue number7
DOIs
StatePublished - Jan 1 2015

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Osteoarthritis
Animal Models
Horses
Proteins
Fluorescence
Period Circadian Proteins
Interleukin 1 Receptor Antagonist Protein
Therapeutics
Capsid
Neutralizing Antibodies
Genes
Cartilage
Joints

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

ScAAVIL-1ra dosing trial in a large animal model and validation of long-term expression with repeat administration for osteoarthritis therapy. / Goodrich, L. R.; Grieger, J. C.; Phillips, J. N.; Khan, N.; Gray, S. J.; McIlwraith, C. W.; Samulski, R. J.

In: Gene Therapy, Vol. 22, No. 7, 01.01.2015, p. 536-545.

Research output: Contribution to journalArticle

Goodrich, L. R. ; Grieger, J. C. ; Phillips, J. N. ; Khan, N. ; Gray, S. J. ; McIlwraith, C. W. ; Samulski, R. J. / ScAAVIL-1ra dosing trial in a large animal model and validation of long-term expression with repeat administration for osteoarthritis therapy. In: Gene Therapy. 2015 ; Vol. 22, No. 7. pp. 536-545.
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