The use of senolytic and anti-fibrotic agents to improve the beneficial effect of bone marrow stem cells for osteoarthritis
Ended Cooperative Agreement Awarded Last action
- Award ID
- UH3AR077748
- Recipient
-
Steadman Philippon Research Institute UEI WGXZN68GYDD5
- Awarding agency
-
National Insititue of Arthritis and Musculoskeletal and Skin Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $4,287,469
Award facts
- Assistance listing
- 93.370 21st Century Cures Act: Regenerative Medicine Initiative
- Completion date
- Funding
-
- $4,030,969.00 Federal
- $256,500.00 Non-federal
- Funding agency
- Office of the Director National Institutes of Health, Department of Health and Human Services
- Place of performance
- Colorado, USA
Award details come from USAspending.gov.
Description
- 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-SS1BLOCKER) 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.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $0 | $0 | |
| Amendment | $551,586 | $0 | |
| Amendment | $600,051 | $0 | |
| Amendment | $521,091 | $0 | |
| Amendment | $100,000 | $0 | |
| Amendment | $521,091 | $0 | |
| Amendment | $156,500 | $0 | |
| Amendment | $156,500 | $0 | |
| Amendment | $156,500 | $156,500 | |
| Amendment | $100,000 | $0 | |
| Amendment | $533,825 | $0 | |
| Amendment | $533,825 | $0 | |
| Original award | $100,000 | $100,000 |
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Quick answers
Who received award UH3AR077748?
UH3AR077748 was awarded to Steadman Philippon Research Institute by National Insititue of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health) on August 1, 2020.
How much is award UH3AR077748 worth?
$4,287,469 has been obligated on UH3AR077748: $4,030,969 in federal funding and $256,500 in non-federal funding.
Which agency awarded UH3AR077748?
National Insititue of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health) awarded UH3AR077748, with funding from Office of the Director (National Institutes of Health).
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