Development of a new advanced platform for personalized treatment of transthyretin amyloid cardiomyopathy
O Iglesias Garcia, A U Ullate-Agote, J Qin, P Montero-Calle, I Anaut-Lusar, E Larequi, N Salterain, J P G Sluijter, M I F Oerlemans, A van Mil, M Garcia de Yebenes, J J Gavira, F Prosper, M M Mazo VegaAbstract
Objectives
Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal multisystem disease, lacking an optimal therapy, stemming from the absence of representative models. Our work aims to provide advanced 3D disease models, for identifying the early mechanisms underlaying disease progression, contributing to the development of more precise and personalised effective treatments and potential cures.
Methods
Human induced pluripotent stem cell (hiPSC)-derived cardiac cells were embedded at high, physiological relevant densities in fibrin hydrogels, incorporating TTR amyloid fibrils and casted into 3D printed scaffolds using Melt Electro Writing (MEW) technology. Response to exposure to different increasing doses of TTR was analyzed. Tissues were maintained for over 4 weeks with a multiparametric analysis conducted on a weekly basis to determine viability, functionality, structure, electrophysiology, and genomic expression profiling.
Results
Biomimetic functional cardiac tissues can be generated using 3D printed MEW scaffolds. The presence of fibrils directly affects human cardiomyocyte function in 3D cardiac constructs, leading to sarcomere disruption and reducing the amplitude and speed of contraction. No differences were found in the cardiac tissues in terms of cell viability after 4 weeks of exposure to the concentrations used. Genes related to cardiac structural organization and function, such as MYL2, SCN5A1, CACNA1C, COL1A1, NPPA and NPPB, were significantly downregulated in tissues exposed to TTR. Interestingly, tissues showed shortened calcium transients after TTR exposure compared to unexposed tissues, suggesting a proarrhythmic behaviour of fibrils, which could correlate with the presence of arrhythmias in some ATTR-CM patients.
Conclusions
We have provided an advanced model of ATTR-CM capable of recapitulating the early stages of the disease, by applying frontline technologies in cell reprogramming, biofabrication and biomaterials, which will contribute to advancing our understanding of the mechanisms of the disease, and help discovering and formulating new treatments.