SEN-OA – Targeting senescent cells in osteoarthritis: an innovative therapeutic approach

We propose a multifaceted approach combining innovative biomedical senescence models, ageing animal studies, human sample analyses and screening for senescence-targeting compounds for clinical application to (i) decipher the role of ageing-associated senescence mechanisms in the appearance of OA and (ii) develop innovative treatments for OA patients. If successful, the project could lead to a first- in-man clinical trial.

We have discussed the proposal with a patient group in Paris, they thought the idea novel and worthwhile. We gained their input to the lay summary. We will have two patient representatives to support the writing of our patient information sheets and to help communicate the findings of the project. They will participate to the scientific advisory board. There are no obvious risks of the project to the patients. Technical risk is minimal as the assays involved are already carried out in our laboratories.

• WP1. A movie dedicated to the presentation of the SEN-OA project and to the feedback of two patient experts of one-day visit of a research laboratory on OA has been made.
• WP2. Several types of samples in 3 non-clinical models of mice and humans with OA have been collected and are under evaluation for expression of senescence markers in various articular tissues.
• WP3. Different in vitro (stem cells, chondrocytes) and in vivo (mouse, zebrafish) models of senescence have been developed. Senolytics are being evaluated in those models.  
• WP4. A preliminary screening was performed with a repurposing library to identify Senolytics and Pro-autophagy modulators in human chondrocytes. Several candidates are available for further validation.

• Boulestreau J, Maumus M, Rozier P, Jorgensen C, Noël D. Mesenchymal stem cell derived extracellular vesicles in aging. Frontiers in Cell and Developmental Biology, 2020; 8: 107
• Malaise O, Tachikart Y, Constantinides M, Mumme M, Ferreira-Lopez R, Noack S, Krettek C, Noël D, Wang J, Jorgensen C, Brondello JM. Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development. Aging (Albany NY) 2019; 11(20): 9128-9146.
• Tachikart Y, Malaise O,  Mumme M, Jorgensen C, Brondello JM. Seno-suppressive molecules as new therapeutic perspectives in rheumatic diseases; Biochem Pharmacol 2019; 165: 126-133.
• Nogueira-Recalde U, Lorenzo-Gómez I, Blanco FJ, Loza MI, Grassi D, Shirinsky V, Shirinsky I, Lotz M, Robbins PD, Domínguez E, Caramés B. Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine 2019; 45: 588-605.
• Vinatier C, Domínguez E, Guicheux J, Caramés B. Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis. Front Physiol. 2018; 25; 9: 706.

Accepted abstracts related to SEN-OA selected at EULAR 2020

Noël D, Invited speaker in session Aging, senescence and osteoarthritis, “Senolytics: are they magic bullets for treating OA?”