Self-Complementary Adeno-Associated Virus–Mediated Interleukin-1 Receptor Antagonist Gene Delivery for the Treatment of Osteoarthritis: Test of Efficacy in an Equine Model
| Autor: | Steven C. Ghivizzani, Margaret E. White, Eric P. Gibbs, Alison J. Morton, E. Viktoria Hyddmark, Mathew Winter, Michael J. Dark, David A. Myara, Yuan Lu, Christopher H. Evans, E. Anthony Dacanay, David M. Nickerson, Gregory B. Foremny, Patrick T. Colahan, Rice B, Elham Nasri, Ted A. Broome, Rachael S. Watson Levings, Ali Zarezadeh, Andrew D. Smith, Padraic P. Levings |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.drug_class Genetic Vectors Arthritis Osteoarthritis medicine.disease_cause Injections Intra-Articular Lesion 03 medical and health sciences 0302 clinical medicine Synovitis medicine Animals Humans Knee Horses Adeno-associated virus Research Articles Genetics (clinical) 030203 arthritis & rheumatology business.industry Gene Transfer Techniques Genetic Therapy Dependovirus Joint effusion medicine.disease Receptor antagonist Disease Models Animal Interleukin 1 Receptor Antagonist Protein 030104 developmental biology Lameness Immunology medicine.symptom business |
| Zdroj: | Human Gene Therapy Clinical Development. 29:101-112 |
| ISSN: | 2324-8645 2324-8637 |
| Popis: | 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(12) 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. |
| Databáze: | OpenAIRE |
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