A Multicenter, Double-Blind, Phase III Clinical Trial to Evaluate the Efficacy and Safety of a Cell and Gene Therapy in Knee Osteoarthritis Patients

Kim, Myung Ku; Ha, Chul‐Won; In, Yong; Cho, Sung Do; Choi, Eui Sung; Ha, Jeong Ku; Lee, Ju Hong; Yoo, Jae Doo; Bin, Seong‐Il; Choi, Choong Hyeok; Kyung, Hee-Soo; Lee, Myung Chul

doi:10.1089/humc.2017.249

Cited by 95 publications

(63 citation statements)

References 30 publications

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“…In this study, 163 patients with Kellgren-Lawrence grade III OA were randomly assigned to receive a single intra-articular injection of TissueGene C or saline. The study met both of its primary outcomes of showing statistically significant improvements in IKDC (+15 versus +5; P < 0.001) and VAS (−25 points versus −10 points; P < 0.001) scores at 52 weeks compared with control 184 . The IKDC and VAS scores were also improved at week-26 and week-39, and statistically significant improvements were seen in secondary clinical outcomes (WOMAC and KOOS) at week-52 compared with control.…”

Section: The Intra-articular Therapy Pipelinementioning

confidence: 87%

“…Data from a multi-centre, double-blind, clinical trial conducted in South Korea revealed that TissueGene C provided long-term clinical benefits compared with placebo 184 . In this study, 163 patients with Kellgren-Lawrence grade III OA were randomly assigned to receive a single intra-articular injection of TissueGene C or saline.…”

Section: The Intra-articular Therapy Pipelinementioning

confidence: 99%

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Intra-articular treatment options for knee osteoarthritis

et al. 2018

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Intra-articular drug delivery has a number of advantages over systemic administration; however, for the past 20 years, intra-articular treatment options for the management of knee osteoarthritis (OA) have been limited to analgesics, glucocorticoids, hyaluronic acid (HA) and a small number of unproven alternative therapies. Although HA and glucocorticoids can provide clinically meaningful benefits to an appreciable number of patients, emerging evidence indicates that the apparent effectiveness of these treatments is largely a result of other factors, including the placebo effect. Biologic drugs that target inflammatory processes are used to manage rheumatoid arthritis, but have failed to translate to OA. A lack of high-level evidence and methodological limitations hinder our understanding of so called ‘stem’ cell therapies and, although the off-label administration of intra-articular cell therapies (such as platelet-rich plasma and bone marrow aspirate concentrate) is common, high-quality clinical data is needed before these treatments can be recommended. A number of promising intra-articular treatments are currently in clinical development in the United States, including small-molecule and biologic therapies, devices, and gene therapies. Although the prospect of new, non-surgical treatments for OA is exciting, the benefits new treatments must be carefully weighed against their costs and potential risks.

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Section: The Intra-articular Therapy Pipelinementioning

confidence: 87%

Section: The Intra-articular Therapy Pipelinementioning

confidence: 99%

Intra-articular treatment options for knee osteoarthritis

et al. 2018

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“…administration of fibroblast growth factor-18 (FGF18) has demonstrated chondroprotective effects in a bovine in vitro model[3], in an in vivo rat model[4] and in a randomized, double-blind, placebo-controlled trial, although pain relief was not achieved[5, 6]. Transforming growth factor-beta1 (TGF-β1) producing human chondrocytes were able to generate cartilage with hyaline-like characteristics in two different animal models[7] and demonstrated clinical benefits in multiple clinical trials[8–12] with small, not statistically significant but encouraging chondroprotective activity[8, 12, 13], and anti-inflammatory activity[13]. SM04690, a Wnt pathway inhibitor, induced chondrocyte differentiation, reduced cartilage catabolism in vitro , and showed chondroprotective activity in a rat model of OA[14], and in humans[15].…”

Section: Introductionmentioning

confidence: 99%

Canine IL4-10 fusion protein provides disease modifying activity in a canine model of OA; an exploratory study

et al. 2019

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Objective An ideal disease modifying osteoarthritis drug (DMOAD) has chondroprotective, anti-inflammatory, and analgesic effects. This study describes the production and characterization of a canine IL4-10 fusion protein (IL4-10 FP) and evaluates its in vivo DMOAD activity in a canine model of osteoarthritis (OA). Design The canine Groove model was used as an in vivo model of degenerative knee OA. Six weeks after OA induction dogs were intra-articularly injected weekly, for ten weeks, with either IL4-10 FP or phosphate buffered saline (PBS). In addition to the use of human IL4-10 FP, canine IL4-10 FP was developed and characterized in vitro , and tested in vivo . Force plate analysis (FPA) was performed to analyze joint loading as a proxy measure for pain. After ten weeks dogs were euthanized and cartilage and synovial tissue samples were analyzed by histochemistry (OARSI scores) and biochemistry (cartilage proteoglycan turnover). Results Repetitive intra-articular injections with human IL4-10 FP led to antibody formation, that blocked its functional activity. Therefore, a canine IL4-10 FP was developed, which completely inhibited LPS-induced TNFα production by canine blood cells, and increased proteoglycan synthesis of canine cartilage in vitro (p = 0.043). In vivo , canine IL4-10 FP restored the, by OA impaired, joint loading (p = 0.002) and increased cartilage proteoglycan content (p = 0.029). Conclusions This first study on the potential DMOAD activity upon prolonged repeated treatment with IL4-10 FP demonstrates that a species-specific variant has anti-inflammatory and chondroprotective effects in vitro and chondroprotective and analgesic effects in vivo . These data warrant further research on the DMOAD potential of the IL4-10 FP.

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“…TGFB1 plays a critical role in skeletal development and adult bone homeostasis18, including bone remodelling19, osteoclast/osteoblast differentiation20,21 and chondrogenesis22. INVOSSA™, a TGFB1 cell and gene therapy in chondrocytes, was associated with significant improvements in function and pain in patients with knee osteoarthritis23.…”

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confidence: 99%

Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data

et al. 2019

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Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we perform a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analysing 4 phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discover 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine map to a single variant. We identify putative effector genes by integrating eQTL colocalization, fine-mapping, human rare disease, animal model, and osteoarthritis tissue expression data. We find enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organisation biological pathways. Ten of the likely effector genes, including TGFB1 , FGF18 , CTSK and IL11 have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.

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A Multicenter, Double-Blind, Phase III Clinical Trial to Evaluate the Efficacy and Safety of a Cell and Gene Therapy in Knee Osteoarthritis Patients

Cited by 95 publications

References 30 publications

Intra-articular treatment options for knee osteoarthritis

Intra-articular treatment options for knee osteoarthritis

Canine IL4-10 fusion protein provides disease modifying activity in a canine model of OA; an exploratory study

Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data

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