Senolytic Agents &Osteoarthritis

• Status: Not yet recruiting
• Trial end date: 2023-12-01
• Target enrollment: 0
• Participant gender: All

Summary

Osteoarthritis is a progressive degenerative disease of the joint leading to cartilage damage, pain and loss of function affecting an estimated 250 million people worldwide and 27 million people in the United States . Currently, there are no effective FDA-approved therapies that are disease modifying interventions to prevent the course of joint destruction due to Osteoarthritis The most prevalent first-line treatment for OA is to mitigate pain and restore function with a combination of weight management, physical therapy, mind-body exercises, and analgesia with paracetamol or NSAIDs (topical or oral) . Another prominent treatment strategy is the use of intra-articular corticosteroids (CS) to reduce pain and inflammation via targeting production of interleukins, leukotrienes and prostaglandins However, the palliative effects of CS for OA are often short-term, can potentially lead to chondral fissuring and promotion of dose-independent structural changes in cartilage, and there are no consistent reports of efficacy .

One novel potential and appealing approach for treating Osteoarthritis is through the local and systemic elimination of senescent cells. Senescent cell burden increases significantly with age and has been shown to promote several age-related pathologies including degenerative joint conditions.

Senescent cells are non-proliferative, resistant to apoptosis, and secrete pro-inflammatory factors that promote disease and systemic aging . Cellular senescence can be induced by a variety of extrinsic and intrinsic signals that leads to the production of a collection of various proinflammatorycytokine and other factors that initiate senescence in neighboring cells and promote disease and tissue dysfunction.

Thus, senescent cells and their associate senescence associated secretory phenotype profiles likely play a role in both the clinical manifestation of OA (pain) and disease pathogenesis (tissue dysfunction and cartilage degradation. The overall safety and efficacy of several senolytic drugs to treat chronic diseases have been demonstrated in several preclinical studies and more recently in phase I-II clinical trials for OA. For example, the senolytic drug Dasatinib is an FDA approved drug for leukemia with few side effects while other senolytic drugs like quercetin and fisetin are naturally occurring plant flavonoids tolerable at relatively high doses . Clinical trials about the use of senolytic agents as therapeutic agents in different clinical cases:-

• Senescent Cell Burden in Hematopoietic Stem Cell Transplant Survivors (Mayo Clinic, NCT02652052 )

• Senolytic Therapy to Modulate Progression of Alzheimer's Disease ( The University of Texas Health Science Center at San Antonio

,NCT04063124)

• Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease:

Effect of Senolytic Agents (Mayo Clinic NCT02848131)

• COVID-FISETIN: Pilot in SARS-CoV-2 of Fisetin to Alleviate Dysfunction and Inflammation (Mayo Clinic NCT04476953)

• Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults ( Mayo Clinic NCT03675724)

• Inflammation and Stem Cells in Diabetic and Chronic Kidney Disease ( Mayo Clinic NCT03325322 ) NLRP3 Inflammasome:- Inflammasomes play a crucial role in innate immunity by serving as signaling platforms which deal with a plethora of pathogenic products and cellular products associated with stress and damage. By far, the best studied and most characterized inflammasome is NLRP3 inflammasome, which consists of NLRP3 (nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3) The hyperactivation of NLRP3 inflammasome is involved in a wide range of inflammatory diseases. The search and development of anti- inflammatory drugs from natural sources of plants has received extensive attention.licorice extract has high activity and wide therapeutic effects.it has reported that glycyrrhizin could ameliorate fibrosis and inflammation via inhibiting NLRP3 inflammasome activation and NF-κB signaling pathway. Aim of work:- To determine the efficacy of Natural senolytic agents and NLRP3 Inflammasome inhibitors for reducing knee symptoms and effusion- synovitis in patients wih symptomatic knee Osteoarthritis and knee effusion /synovitis.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Assiut University
• Treatments: Glycyrrhizic Acid; Quercetin

Criteria

Inclusion Criteria:

• male or female, ages 40-80;

• Are willing to comply with all study related procedures and assessments;

• ambulatory as defined by ability to complete functional performance testing;

• Radiographic evidence of Kellgren-Lawrence grade II-IV osteoarthritis in one or both knees;

• Scores 4-10 on the Numerical Rating Scale (NRS) for pain;

Exclusion Criteria:

• Pregnant or nursing females.

• Subjects who do not have the capacity to consent themselves.

• Subjects who are unable to tolerate oral medication.

• Subjects with uncontrolled medical conditions .

• Surgery on the Study Knee in the past 6 months.

• intra-articular injection of corticosteroids or hyaluronic acid in the past 6 months.

• subjects with significant liver or renal disease.