Abstract
Characterization of a novel human placental tissue-derived biologic, PTP-001, which is in development as a candidate therapeutic for the treatment of osteoarthritis symptoms and pathophysiology. Human placental tissues from healthy donors were prepared as a particulate formulation, PTP-001. PTP-001 extracts were assayed for the presence of disease-relevant biofactors which could have beneficial effects in treating osteoarthritis. PTP-001 eluates were tested in human chondrocyte cultures to determine effects on the production of a key collagen-degrading matrix metalloproteinase, MMP-13. PTP-001 eluates were also assessed for anti-inflammatory potential in human monocyte/macrophage cultures, as well as for growth-stimulating anabolic effects in human synoviocytes. The in vivo effects of PTP-001 on joint pain and histopathology were evaluated in a rat model of osteoarthritis induced surgically by destabilization of the medial meniscus. PTP-001 was found to contain an array of beneficial growth factors, cytokines and anti-inflammatory molecules. PTP-001 eluates dose-dependently inhibited the production of chondrocyte MMP-13, and the secretion of proinflammatory cytokines from monocyte/macrophage cultures. PTP-001 eluates also promoted proliferation of cultured synovial cells. In a rat osteoarthritis model, PTP-001 significantly reduced pain responses throughout 6 weeks post-dosing. The magnitude and duration of pain reduction following a single intraarticular treatment with PTP-001 was comparable to that observed for animals treated with a corticosteroid (active control). For rats dosed twice with PTP-001, significant reductions in cartilage histopathology scores were observed. PTP-001 represents a promising biologic treatment for osteoarthritis, with a multi-modal mechanism of action that may contribute to symptom management and disease modification.
Highlights
Symptomatic osteoarthritis (OA) is generally defined by the occurrence of pain, aching, or stiffness in a joint with documented radiographic disease, including degeneration of the articular cartilage
Addition of PTP-001 eluates resulted in a significant reduction of matrix metalloproteases (MMPs)-13 production by human OA chondrocytes
Concurring results for reduction of MMP-13 levels were observed for a total of N 1⁄4 6 technical replicates, wherein PTP-001 eluates were tested at doses ranging from 2.5 mg/ml to 20 mg/ml, indicating that PTP-001 may have a protective role in OA joints by inhibiting MMP-13 expression, and associated collagen/extracellular matrix (ECM) degradation
Summary
Symptomatic osteoarthritis (OA) is generally defined by the occurrence of pain, aching, or stiffness in a joint with documented radiographic disease, including degeneration of the articular cartilage. Many patients undergo total joint replacement which, while often helping to alleviate the severity of pain and loss of function, is a procedure not without the potential risks associated with surgery, the potential for lack of effectiveness, and with a possible requirement for later revision surgery ( in younger patients)[4]. Attempts to develop novel disease-modifying therapies for OA have failed, principally due to lack of clinical efficacy or safety issues. Such treatments have generally focused on modulation of a single target (e.g., a specific cytokine or enzyme/protease) whereas OA is a complex, multifactorial disease process
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