Genistein in trAnSthyretin recePtor Amyloid caRdiomyopathy

Amyloid Cardiomyopathy

This Phase 1b/2a study aims to investigate the safety and efficacy of genistein in patients with Transthyretin (TTR) Amyloidosis. The focus is on its impact on inflammatory and cardiometabolic biomarkers, along with the effects on cardiac function and exercise capacity. Blood samples will be collected at baseline, following each dose of genistein, and after a six-week placebo washout period. These samples will undergo extensive analyses, including profiling for inflammatory cytokines and novel molecular markers, and routine tests like CBC, Chem 7, LFT, HbA1c, NT-proBNP, CRP, troponin T, and serum TTR. RNA-seq analyses on peripheral blood mononuclear cells (PBMCs) and isolation of plasma exosomes for inflammatory biomarkers are also part of the protocol. Following ESC/AHA guidelines, echocardiography will assess cardiac structure and function, focusing on the left and right ventricles and valvular function. Additionally, exercise capacity will be evaluated through a standardized 6-minute walk test, and NT-proBNP levels will be measured as a cardiac stress biomarker. The trial will include an 18-week follow-up period post-enrolment, with the primary endpoint being the change in inflammatory markers from baseline to three months. Secondary endpoints are cardiac function and exercise capacity changes over the same timeframe. This study aims to provide significant insights into genistein's therapeutic potential for TTR Amyloidosis and its broader implications in managing heart failure. Following ethical committee approval and written informed consent, the Investigators aim is to enroll 40 participants. This is an open-label study. Each patient will receive genistein by mouth: 250 mg twice a day for 4 weeks (500 mg total/day), 500 mg twice a day for 4 weeks (1000 mg total/day), and 750 mg twice a day (1500 mg total/day) for an additional 4 weeks. This will be followed by a 6-week washout period to conclude the study. An 18-month study is anticipated based on the average enrollment rates. Results from this study are expected to offer critical insights for future larger studies.

BACKGROUND. Heart Failure (HF) is a complex clinical syndrome when the heart cannot meet the metabolic demands of the body. HF is a growing health and economic burden in the United States. Between 2013 to 2017, there were over 1.2 million hospitalizations per year and costs of over $30 billion per year. The prognosis of HF is quite poor, with the number of deaths per year increasing from 275,000 in 2009 to 310,000 in 2014. HF is caused by ischemic cardiomyopathy, valvular disease, and non-ischemic cardiomyopathy, which includes infiltrative cardiac disease such as amyloidosis. The link between inflammation and HF is well characterized and plays a significant role in heart failure. The immune system is activated in response to myocardial injury, decreased peripheral perfusion, or neurohormonal activation. Cytokines are released from inflammatory cells and destabilize cardiovascular function. When a cardiomyocyte is damaged by infarction or stretch from volume or pressure overload, the surrounding myocytes secrete inflammatory cytokines that further exacerbate HF. Inflammatory cytokines serve as reliable indicators of HF severity, providing prognostic value and a means to assess the effectiveness of therapeutic interventions. A host of inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-a (TNF-alpha), and interferon g (IFN-gamma), have been identified as key players in the pathogenesis of HF. Chronic HF management includes correcting the underlying cause, treating symptoms, and long-term pharmacological and device therapy. In the chronic setting, pharmacological interventions such as β-blockers, ACE inhibitors, aldosterone antagonists, and sodium-glucose cotransporter-2 inhibitors (SGLT2i) combined with implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) can markedly improve symptoms and survival. GENISTEIN Genistein, a soybean derivative, can potentially reduce inflammation and oxidative stress, as demonstrated in numerous preclinical models. It has been studied extensively and has no known adverse side effects. Moreover, it does not significantly interact with cardiac medications. Genistein has emerged as an interesting compound due to its anti-inflammatory and antioxidant properties. Acting as an antagonist to cannabinoid receptor 1, genistein can influence several pathways implicated in the exacerbation of heart failure, primarily inflammation and oxidative stress. Evidence from preclinical models has highlighted genistein's capacity to modulate immune responses and alleviate oxidative stress, which are instrumental in the inflammatory processes underlying heart failure. Moreover, genistein has demonstrated cardio-protective effects in various in vitro and animal studies, suggesting a therapeutic potential that warrants further clinical exploration. ATTR PATHOGENESIS Transthyretin amyloid cardiomyopathy (ATTR-CM) is an often-overlooked form of amyloidosis that leads to restrictive cardiomyopathy and progressive heart failure. This condition predominantly affects the elderly and patients with hypertrophic cardiomyopathy. ATTR-CM results from the aggregation of misfolded transthyretin (TTR) proteins, which form amyloid fibrils that deposit in the cardiac tissue. These deposits can disrupt normal cardiac architecture and function, precipitating diastolic dysfunction and heart failure. The misfolding and aggregation of TTR, a protein responsible for transporting thyroxine and retinol-binding protein, can be attributed to genetic mutations or age-related changes. genistein has been shown to bind and stabilize TTR, potentially inhibiting its misfolding and subsequent fibril formation. This stabilization presents a novel approach that could impede the progression of ATTR-CM. STUDY RATIONALE A notable pathogenic process associated with aging or mutation involves the misfolding of Transthyretin (TTR), leading to its aberrant assembly into amyloid. This misassembly causes conditions such as amyloidosis, familial amyloid neuropathy, and amyloid cardiomyopathy. Small molecules have been found to stabilize the native tetramer by binding to the thyroid hormone binding sites of TTR. The current clinical trial is designed to address a pivotal gap in heart failure treatment by integrating genistein as an adjunct therapy alongside the standard of care, tafamidis. By targeting both the inflammatory mechanisms implicated in heart failure and the molecular pathogenesis of ATTR-CM, the study positions genistein as a potential modifier of disease progression. Recognized for its commendable safety profile and the absence of reported major adverse side effects, genistein holds the potential to address ATTR-CM. The adjunctive use of genistein could enhance tafamidis therapy, offering a dual approach to stabilize TTR and mitigate inflammation. This study is poised to contribute significantly to the heart failure therapeutic landscape, potentially improving outcomes for patients with ATTR amyloid cardiomyopathy. By exploring genistein's role in conjunction with established therapies, this research may pave the way for novel, more effective treatment regimens for heart failure, particularly in those with or at risk for ATTR-CM.

No related papers found yet.

Canada