The Use of Senolytic and Anti-Fibrotic Agents to Improve the Beneficial Effect of Bone Marrow Stem Cells for Osteoarthritis - Abstract: Osteoarthritis (OA) is a progressive joint disease leading to cartilage damage, pain and loss of
function. While many stem cell therapies for OA are under investigation, none are currently FDA-approved for
modifying the course of the disease. Of the many adult stem cell types potentially applicable to OA, bone marrow
stem cells (BMSCs) from bone marrow aspirate concentrate (BMC) are the most clinically translatable (and are
already in clinical use) since they can be harvested using minimally invasive technology and do not require in
vitro expansion. There is, however, significant potential for improving efficacy of BMSC treatment for OA. The
number of senescent cells in BMC increases with age and OA, and these cells release pro-inflammatory
cytokines/chemokines, proteases, and other senescence-associated secretory phenotypes (SASP) that can
impair stem cell function and likely contribute to OA development/progression. Dr. Kirkland’s laboratory (co-
investigator) has identified compounds that specifically kill senescent cells, abrogating systemic SASP factors.
We have shown that these senolytic agents can delay OA in a preclinical model. We have also shown that
blocking fibrosis with Losartan (a TGF-β1blocker) can improve cartilage repair by promoting regeneration of
hyaline cartilage while reducing the amount of fibrocartilage. Thus, we hypothesize that administration of
senolytic and/or anti-fibrotic agents will enhance the beneficial effect of BMSCs for treating OA. We propose to
perform, a randomized clinical trial at The Steadman Clinic (TSC) and Steadman Philippon Research Institute
(SPRI). This phase I/II trial will evaluate the safety and efficacy of Fisetin (a senolytic dietary supplement) and
Losartan (an anti-fibrotic drug), used either individually or in combination, for improving the clinical efficacy of
BMSCs in the treatment of knee osteoarthritis. The senolytic (Fisetin 1000mg/day, previously FDA IND
approved) regimen will be cycles of 2 days on/28 days off, administered before and 3 months after BMSC
treatment. The anti-fibrotic (Losartan, 25mg/day, previously IND-exempted) will be administered for 30 days
starting immediately after BMSC treatment. OA knee joints will undergo MRI at baseline and 18 months post-
treatment to assess changes in cartilage morphology and structure over time. Patient-reported outcomes for
pain and function will be collected at baseline and 3, 6, 12 & 18 months. Joint and cartilage function will be
assessed using video-motion analysis at baseline and 18 months. OA biomarkers related to cartilage
degeneration, inflammation and pain will be assessed at baseline and 18 months. Blood and synovial fluid will
be evaluated at baseline, 4 days and 18 months after treatment to assess changes in cellular senescence and
OA biomarkers. This trial will build upon a currently active clinical trial on orthobiologics for OA treatment at
SPRI (utilizing the same patient population and outcomes assessments), demonstrating the ability of our teams
to perform the proposed study and also leveraging the combined trials to effectively provide a 6-arm,
comprehensive assessment of biological therapies for improving treatment of OA.
