scAAVIL-1ra dosing trial in a large animal model and validation of long-term expression with repeat administration for osteoarthritis therapy
| Autor: | Nadia N. Khan, Jennifer N Phillips, Richard Jude Samulski, C. W. McIlwraith, Steven J. Gray, Laurie R. Goodrich, Joshua C Grieger |
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| Rok vydání: | 2015 |
| Předmět: |
Cartilage
Articular Pathology medicine.medical_specialty Genetic Vectors Dose-Response Relationship Immunologic Gene Expression Osteoarthritis Pharmacology Article Green fluorescent protein Therapeutic approach Immune system Genetics medicine Animals Horses Vector (molecular biology) Dosing Molecular Biology Carpal Joints biology business.industry Synovial Membrane Genetic Therapy medicine.disease Antibodies Neutralizing Disease Models Animal Interleukin 1 Receptor Antagonist Protein Toxicity biology.protein Molecular Medicine Antibody business |
| Zdroj: | Gene Therapy. 22:536-545 |
| ISSN: | 1476-5462 0969-7128 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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