(494.4) Liver-Heart Microphysiological Organoid Model for the Study and Treatment of Cardiac Amyloidosis

Poster Board Number: A157

Marcus Williams (Johns Hopkins School of Medicine), Will Jeffreys (Johns Hopkins School of Medicine), Vivek Jani (Johns Hopkins School of Medicine), Brian Lin (Johns Hopkins School of Medicine), Mark Ranek (Johns Hopkins School of Medicine)

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a form of restrictive heart disease resulting from the aggregation of amyloid fibrils, that confers substantial morbidity and mortality. Transthyretin (TTR) forms a homotetrameric protein complex generated in the liver and is involved in retinol and vitamin A transfer. However, it can dissociate into monomers, that when taken up by the heart, can lead to ATTR-CM. A TTR valine-122 to isoleucine (TTRV122I) mutation is the predominant hereditary form in the U.S., present in 4% of African Americans, that destabilizes the TTR homotetrameric complex. In 2019 the FDA approved tafamidis, a first in class therapy for ATTR-CM that stabilizes the TTR homotetramer, slowing but not arresting its dissociation into cytotoxic monomers or preventing TTR monomer deposits. Treatments that achieve the latter have yet to reach clinical settings and could further improve outcomes of ATTR-CM patients. The lack of pre-clinical human based models has severely limited mechanistic studies of ATTR-CM and presents a major obstacle to developing translational therapies. We have addressed this by developing a new in vitro human cell model of TTRV122I via a novel microfluidics approach to co-culture hepatic organoids expressing TTRV122I and human iPSC derived cardiomyocyte (hiPSC-CM) organoids. This engineered device allows for the establishment of two distinct chambers containing both hepatic or cardiac organoids that are connected via a series of microfluidic channels to simulate circulation. With this approach, we create a physiologically relevant environment where hepatocytes synthesize and secrete TTRV122I at a concentration range of 3-7 mM, as observed in human ATTR-CM patients, that can then be taken up by cardiomyocytes. Once taken up, the cardiomyocytes develop features of ATTR-CM, namely oxidative stress, protein aggregation, cytotoxicity, and abormal conductance. We assess cardiomocyte function via IonOptix cytomotion. We observed diastolic impairment in cardiomyocytes incubated with TTRV122I but not in our control cells. Notably, ATTR-CM patients exhibit marked diastolic impairment and conduction system disease. In addition, this platform allows us to pace the cardiomyocyte organoids, and using optical tracking methods, look at waveforms and calcium transience. Thus, our in vitro system accurately recaptilates many key features of human ATTR-CM and provides a new plateform to test novel therapeutic interventions.

This work was supported by grants from the National Institutes of Health R25GM109441, the American Heart Association 90078982, 90091225, 20POST35180102 and the Amyloidosis Foundation 90086377.