Alnylam Act®: Heterogenous Disease Manifestations of Hereditary Transthyretin-Mediated Amyloidosis

Abstract

heart and vascular tissue. TRPC6 participates in the pathogenesis of cardiac hypertrophy as a pathological response to chronic mechanical stress. Chronic activation has been found to promote cardiac fibrosis leading to heart failure. Overall these data suggest that TRPC6 variants could be associated with increased risk of doxorubicininduced cardiotoxicity. Hypothesis: Tests to determine which patients may progress to cardiomyopathy and heart failure are currently lacking and there are no targeted treatments to prevent cardiomyopathy in these patients. Methods: In preliminary in vivo data, B6.129 wild-type mice (10 females, 10 males) were treated with either 6x intraperitoneal saline or 4mg/kg doxorubicin injections (cumulative dose of 24mg/ kg). Results: Our in vitro preliminary data show that inhibition of TRPC6 using the TRPC6 inhibitor GsMTx-4 in human iPSC-derived cardiomyocytes significantly reduced doxorubicin-induced apoptosis (p<0.0001). In vivo we found doxorubicin decreased HW/BW (p=0.008) and HW/TL (p=0.0004) ratios and increased cardiac vacuolation (p=<0.001) in male mice treated with doxorubicin compared to controls. Higher HW/BW ratio were also observed in TRPC6 knock out mice treated with doxorubicin compared to wild-type mice (p=0.005). Additionally, we found that doxorubicin-induced cardiac injury was significantly reduced in TRPC6 knock-out mice compared to wild-type mice based on reduced vacuolation (p=0.0004 males, p=0.03 females). Furthermore, a significant decrease in stroke volume (p=0.007), diastolic volume (p=0.01) and cardiac output (p=0.004) were found at day 21 post treatment in wild-type male mice treated with doxorubicin compared to control and TRPC6 knock-out mice. Conclusions: Our results suggest that TRPC6 could be a novel therapeutic target in the prevention of chemotherapy-induced cardiomyopathy and heart failure. Genetic mapping of TRCP6 functional variants may provide a new screening tool to determine which cancer patients are at increased risk of developing heart failure and may benefit from increased cardiac monitoring and TRPC6-specific therapies.Introduction: An estimated 3.1 cases of myocarditis were diagnosed in 2017 worldwide. Patients with myocarditis are at risk of sudden death from acute heart failure and may progress to dilated cardiomyopathy (DCM) and chronic heart failure, often requiring a heart transplant. Currently, no disease-specific therapies exist to reduce myocarditis or prevent progression to DCM. Hypothesis: Exosomes extracellular vesicles released from stem cells or other cells like platelets are thought to be able to confer cardioprotection. Because more men develop myocarditis (3.5:1 men to women) and DCM we hypothesized that purified exosome product (PEP) from premenopausal women (pmPEP) could improve and/or prevent myocarditis and prevent progression to dilated cardiomyopathy (DCM) using a preclinical mouse model of myocarditis/DCM. Methods: We administered PEP (from men and women of all ages), pmPEP (premenopausal women) or control ip to male BALB/...