| Autor: |
Watson Levings RS; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida., Smith AD; 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida., Broome TA; 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida., Rice BL; 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida., Gibbs EP; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida., Myara DA; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida., Hyddmark EV; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida., Nasri E; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida., Zarezadeh A; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida., Levings PP; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida., Lu Y; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida., White ME; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida., Dacanay EA; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida., Foremny GB; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida., Evans CH; 3 Rehabilitation Medicine Research Center, Mayo Clinic , Rochester, Minnesota., Morton AJ; 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida., Winter M; 4 Department of Small Animal Clinical Sciences, University of Florida , Gainesville, Florida., Dark MJ; 5 Department of Infectious Diseases and Pathology, University of Florida , Gainesville, Florida., Nickerson DM; 6 Department of Statistics and Actuarial Science, University of Florida , Gainesville, Florida., Colahan PT; 2 Department of Large Animal Clinical Sciences, University of Florida , Gainesville, Florida., Ghivizzani SC; 1 Department of Orthopedics and Rehabilitation, University of Florida , Gainesville, Florida. |
| Abstrakt: |
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. |
