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      Combinatorial Prg4 and Il-1ra Gene Therapy Protects Against Hyperalgesia and Cartilage Degeneration in Post-Traumatic Osteoarthritis

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          Abstract

          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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          Most cited references27

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          Bone remodelling in osteoarthritis.

          The classical view of the pathogenesis of osteoarthritis (OA) is that subchondral sclerosis is associated with, and perhaps causes, age-related joint degeneration. Recent observations have demonstrated that OA is associated with early loss of bone owing to increased bone remodelling, followed by slow turnover leading to densification of the subchondral plate and complete loss of cartilage. Subchondral densification is a late event in OA that involves only the subchondral plate and calcified cartilage; the subchondral cancellous bone beneath the subchondral plate may remain osteopenic. In experimental models, inducing subchondral sclerosis without allowing the prior stage of increased bone remodelling to occur does not lead to progressive OA. Therefore, both early-stage increased remodelling and bone loss, and the late-stage slow remodelling and subchondral densification are important components of the pathogenetic process that leads to OA. The apparent paradoxical observations that OA is associated with both increased remodelling and osteopenia, as well as decreased remodelling and sclerosis, are consistent with the spatial and temporal separation of these processes during joint degeneration. This Review provides an overview of current knowledge on OA and discusses the role of subchondral bone in the initiation and progression of OA. A hypothetical model of OA pathogenesis is proposed.
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            Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.

            To evaluate the clinical response, safety, and tolerability of a single intraarticular injection of anakinra in patients with symptomatic osteoarthritis (OA) of the knee. Patients with OA of the knee were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1:2 to receive a single intraarticular injection of placebo, anakinra 50 mg, or anakinra 150 mg in their symptomatic knee. Patients were evaluated for 12 weeks postinjection. The primary end point was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score from baseline to week 4. Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs. Pharmacokinetic parameters were assessed in a subset of patients. Of 170 patients who enrolled, 160 (94%) completed the study. The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50 mg of anakinra (P = 0.67) or 150 mg of anakinra (P = 0.77). Anakinra was well tolerated. No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported. No clinically significant trends were noted in laboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminal half-life of anakinra in serum after intraarticular injection was approximately 4 hours. Anakinra was well tolerated as a single 50-mg or 150-mg intraarticular injection in patients with OA of the knee. However, anakinra was not associated with improvements in OA symptoms compared with placebo.
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              Progress in intra-articular therapy.

              Diarthrodial joints are well suited to intra-articular injection, and the local delivery of therapeutics in this fashion brings several potential advantages to the treatment of a wide range of arthropathies. Possible benefits over systemic delivery include increased bioavailability, reduced systemic exposure, fewer adverse events, and lower total drug costs. Nevertheless, intra-articular therapy is challenging because of the rapid egress of injected materials from the joint space; this elimination is true of both small molecules, which exit via synovial capillaries, and of macromolecules, which are cleared by the lymphatic system. In general, soluble materials have an intra-articular dwell time measured only in hours. Corticosteroids and hyaluronate preparations constitute the mainstay of FDA-approved intra-articular therapeutics. Recombinant proteins, autologous blood products and analgesics have also found clinical use via intra-articular delivery. Several alternative approaches, such as local delivery of cell and gene therapy, as well as the use of microparticles, liposomes, and modified drugs, are in various stages of preclinical development.
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                Author and article information

                Journal
                Hum Gene Ther
                Hum. Gene Ther
                hum
                Human Gene Therapy
                Mary Ann Liebert, Inc., publishers (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                1043-0342
                1557-7422
                01 February 2019
                08 February 2019
                : 30
                : 2
                : 225-235
                Affiliations
                [ 1 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
                [ 2 ]Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, Texas.
                [ 3 ]H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas.
                [ 4 ]Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas.
                [ 5 ]Department of Pathology, Baylor College of Medicine, Houston, Texas.
                Author notes
                [ † ]

                AS and MWG contributed equally to this work.

                [*] [ * ] Correspondence: Dr. Brendan H. L. Lee, Department of Molecular and Human Genetics, One Baylor Plaza, ABBR-R814, Baylor College of Medicine, Houston, TX 77030. blee@ 123456bcm.edu
                Article
                PMC6383580 PMC6383580 6383580 10.1089/hum.2018.106
                10.1089/hum.2018.106
                6383580
                30070147
                5b9645ed-8d77-4409-8d57-85b50e07471a
                Copyright 2019, Mary Ann Liebert, Inc., publishers
                History
                : 23 May 2018
                : 25 July 2018
                Page count
                Figures: 5, References: 41, Pages: 11
                Categories
                Research Articles

                gene therapy,osteoarthritis,interleukin-1 receptor antagonist,proteoglycan 4,lubricin,helper-dependent adenovirus

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