0870: Targeting Peroxisome Proliferator-Activated Receptor α Is a Disease-Modifying Therapy for Osteoarthritis

Uxía nogueira Recalde¹, Patricia Díaz rodríguez², Francisco J. Blanco³, Eduardo Dominguez Medina⁴ and Beatriz Carames⁵, ¹Unidad de Biología del Cartílago, Grupo de Reumatología, Instituto de Investigación Biomedica de A Coruña (iNIBIC), A Coruña, Spain, ²Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Pharmacy School, Santiago de Compostela, Spain, ³Rheumatology department, Complexo Hospitalario Universitario A Coruña (CHUAC). Instituto de Investigación Biomédica A Coruña (INIBIC), A Coruña, Spain, ⁴Center for Research in Molecular Medicine and Chronic Diseases, Santiago de Compostela, Spain, ⁵Unidad de Biología del Cartílago, Grupo de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain

Background/Purpose: Disease-modifying therapeutic agents to prevent progression of Osteoarthritis (OA) are an urgent clinical need. Targeting senescence and autophagy in chondrocytes with small molecules is a useful strategy to prevent against chondrocyte death, cartilage aging and OA. Fenofibrate (FN), a peroxisome proliferator activated receptor α (PPARα) agonist employed as a therapy for dyslipidemiaswas identified as a senolytic and pro-autophagy molecule showing chondroprotective properties. Here, we evaluated the efficacy of FN in preclinical models as a disease modifying therapy targeting lipid metabolism for OA. To test the effect of this mechanism, FN was administered by both oral route and intra-articular delivery in surgical models of OA.

Methods: Surgical OA was performed by transection of the medial meniscotibial ligament and the medial collateral ligament in the right knee of 4 months-old C57BL/6 male mice. Left knee was employed as a Sham knee. Mice were randomized according to body weight in two groups for oral administration of FN (O-FN) [Vehicle group (DMSO), N=8 and Treated group (100 mg/kg body weight/day, daily, N=8). An intra-articular drug delivery by extended-release of FN in microspheres for 3 months (IA-FN) was developed to 1) to extend the delivery of FN, which is insoluble in water 2) to provide direct access to the joint enhancing the bioavailability in damaged tissue, and 3) to diminish the effects of systemic administration. Mice were divided into three groups for IA-FN efficacy study [Vehicle group (empty microspheres), N=8, Treated group 1 (1 µg FN) and Treated group 2 (10 µg FN). Determination of pain was performed by using the incapacitance test to measure pain by assessing the dynamic weight bearing of spontaneous postural changes. Pain was evaluated every two weeks until euthanasia. Histopathological changes in articular cartilage and synovium were evaluated. The target engagement studies were performed by immunohistochemistry.

Results: In a preclinical model of OA in mice, the treatment with O-FN did not induce changes in body weight and no liver toxicity occurred after the treatment. The histopathological changes in joint cartilage were significantly reduced in the FN treated group (P < 0.05). In addition, the histological evaluation showed a significant decrease in synovitis after O-FN (P < 0.05). This protective effect was correlated with increased expression of PPARα in mouse knee joints after O-FN treatment (P < 0.001). The IA-FN was prepared and comprehensively characterized. IA-FN comprises a PLGA matrix in an optimized ratio, adequate size, appropriate molecular weight, and exhibits a 3-month extended-release profile in human synovial fluid. The preclinical results showed a reduction of joint pain after intra-articular injection of FN (P < 0.01). Moreover, IA-FN improved joint function (P < 0.01) compared to vehicle condition, suggesting that IA-FN is a disease-modifying therapy for OA.

Conclusion: These findings support further non-clinical regulatory studies to develop IA-FN formulation as a candidate therapy for OA. A GMP manufactured formulation could be used to test the safety of this treatment in patients with OA of the Knee in a Phase 1 clinical trial.


U. nogueira Recalde: None; P. Díaz rodríguez: None; F. Blanco: None; E. Dominguez Medina: None; B. Carames: None.