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Regenerative Options for Knee Osteoarthritis Cellular Medicine Chris Evans PhD REHABILATATION MEDICINE RESEARCH CENTER
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DISCLOSURES Orthogen AGSupervisory Board TissueGene IncScientific Advisory Board (IP; licensing fee; honorarium) Aldabra LLCCo-Founder Research funded by NIH, DoD, AO Foundation
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OSTEOARTHRITIS HAS ALWAYS BEEN INCURABLE AND DIFFICULT TO TREAT “Osteoarthritis is an easy disease to take care of. When the patient walks in the front door, I walk out the back door”. Sir William Osler (1849 – 1919)
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Normal Joint
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Osteoarthritic Joint
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PATHOLOGIES Synovial thickening and inflammation Changes to bone Osteophytes Sub-chondral sclerosis Cysts Loss of articular cartilage SYMPTOMS Pain Loss of Function
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PATHOLOGY POTENTIAL SynovitisHigh Osseous ChangesPotentially High Cartilage LossVery Difficult POTENTIAL INTERVENTION IN MAJOR OA PATHOLGIES
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Unlike many other tissues in the body, such as bone, articular cartilage has no intrinsic repair capacity. WHY?
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LOW MAG. MEDIUM MAG. HIGH MAG.
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Articular cartilage has no intrinsic repair capacity because: Avascular Aneural Alymphatic Complex architecture No stem cells (?)
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SEVERELY OSTEOARTHRITIC CARTILAGE
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INTRA-ARTICULAR THERAPY Intuitively attractive for OA – No systemic sequelae – Limited number of affected joints – Higher local drug concentration – Reduced extra-articular side-effects – Reduced cost But more difficult than robbing banks* *Evans CH: Drug delivery to chondrocytes Osteoarthritis Cartilage, 2015
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HALF LIVES OF MOLECULES IN JOINTS Acridine orange (MW 370 Da) 0.23 h NSAIDs and soluble steroids 1- 4 h Anakinra (MW 17 kDa) ~ 4 h Albumin (MW 67 kDa) 1.23 h HA (MW 3x10 6 Da) 26.3 h
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CELLULAR MEDICINE Do cells remain in joint after intra-articular injection? Do they provide therapeutic effect? Do they provide regenerative effect?
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CANDIDATES FOR INTRA-ARTICULAR CELL THERAPY Synovial fibroblasts Chondrocytes Mesenchymal stem/stromal cells (MSCs)
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WHAT IS A STEM CELL? STEM CELLS HAVE TWO IMPORTANT PROPERTIES: 1. They undergo assymetric cell division and thereby self-renew 2. They give rise to other cell types
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Mesenchymal Stem (Stromal) Cell
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MSCs AS A SOURCE OF TROPHIC FACTORS
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MSCs ARE ALSO IMMUNOSUPPRESSIVE CAN THEY BE SUCCESSFULLY ALLOGRAFTED? UNIVERSAL DONOR?
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Visited 10/01/15 Allogeneic 6 Autologous10 Marrow MSCs 11 (BMC* 1) Adipose MSCs 2 (SVF** 1) Umbilical Cord MSCs 3 Phase I or I/II15 Phase II 3 * Bone marrow concentrate ** Stromal vascular fraction Commercialized in Veterinary Medicine
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Recombinant Transforming Growth Factor- 1 Pellet of marrow MSCs Pellet of cartilage IN VITRO CHONDROGENESIS ~ 1 month
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Recombinant TGF- 1 Adenovirus TGF- 1 Adenovirus TGF- 1 Pellet of marrow MSCs Pellet of cartilage IN VITRO CHONDROGENESIS BY GENE TRANSFER ~ 1 month
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OA gene therapy protocol of TissueGene* Phase III trials in USA and Korea Uses allograft chondrocytes expressing TGF- *CHE is on SAB
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* CHE on SAB of TissueGene * INVOSSA™
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Current Surgical Repair Methods Mosaicplasty (OATS) (osteochondral plugs) Allograft (osteochondral plugs) Allograft (living cartilage fragments) AUTO/ALLO-GRAFTING CELL THERAPY Autologous Chondrocyte Implantation (ACI) Microfracture BUT NOT IN OSTEOARTHRITIS
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Interleukin-1 Inhibition of Chondrogenesis Brackets: p<0.05 (n=4)
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INTERLEUKIN-1 (IL-1) A Mediator of Pathology in OA Inflammatory Promotes destruction of cartilage Inhibits chondrogenesis Alters bone turnover Involved in pain
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AAV.IL-1Ra IL-1Ra
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REGENERATION CELLS MORPHOGENS MECHANICAL FACTORS SCAFFOLDS
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REGENERATIVE REHABILITATION
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THANK YOU REHABILATATION MEDICINE RESEARCH CENTER
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