期刊
HUMAN GENE THERAPY
卷 30, 期 2, 页码 225-235出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2018.106
关键词
helper-dependent adenovirus; lubricin; proteoglycan 4; interleukin-1 receptor antagonist; osteoarthritis; gene therapy
资金
- National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [1F31AR067609]
- Cell and Gene Therapy T32 program [T32HL092332]
- Translational Biology and Molecular Medicine T32 program [T32GM088129]
- Howard Hughes Medical Institute Med-into-Grad Program
- BCM Intellectual and Developmental Disabilities Research Center from the Eunice Kennedy Shriver National Institute of Child Health AMP
- Human Development [HD024064]
- BCM Advanced Technology Cores
- NIH [AI036211, CA125123, RR024574]
- Rolanette and Berdon Lawrence Bone Disease Program of Texas
- BCM Center for Skeletal Medicine and Biology
- Pamela and David Ott Center for Heritable Disorders of Connective Tissue
- Canadian Institutes of Health Research
Osteoarthritis (OA) is a degenerative disease of synovial joints characterized by progressive loss of articular cartilage, subchondral bone remodeling, and intra-articular inflammation with synovitis that results in chronic pain and motor impairment. Despite the economic and health impacts, current medical therapies are targeted at symptomatic relief of OA and fail to alter its progression. Given the complexity of OA pathogenesis, we hypothesized that a combinatorial gene therapy approach, designed to inhibit inflammation with interleukin-1 receptor antagonist (IL-1Ra) while promoting chondroprotection using lubricin (PRG4), would improve preservation of the joint compared to monotherapy alone. Employing two surgical techniques to model mild, moderate and severe posttraumatic OA, we found that combined delivery of helper-dependent adenoviruses (HDVs), expressing IL-1Ra and PRG4, preserved articular cartilage better than either monotherapy in both models as demonstrated by preservation of articular cartilage volume and surface area. This improved protection was associated with increased expression of proanabolic and cartilage matrix genes together with decreased expression of catabolic genes and inflammatory mediators. In addition to improvements in joint tissues, this combinatorial gene therapy prolonged protection against thermal hyperalgesia compared to either monotherapy. Taken together, our results show that a combinatorial strategy is superior to monotherapeutic approaches for treatment of posttraumatic OA.
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