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American Heart Association

  58
  2


Final ID: We025

Human Engineered Heart Tissues Demonstrate Clinically-Relevant Disease indicators of Duchenne Muscular Dystrophy

Abstract Body: Accurate in vitro modeling of healthy and disease conditions is crucial for assessing the safety and efficacy of novel therapeutics before clinical trials. For cardiac diseases, direct evaluation of muscle contraction is a reliable indicator of overall tissue function, however, this often necessitates expensive and low-throughput non-human in vivo models. Moreover, animal models may not accurately predict human responses to compound exposure.
Here, we have developed a turnkey platform for facile fabrication of 3D engineered heart tissues (EHTs) that enables label-free, push-button measurements of contractility. The system allows for customized stimulation protocols to individual constructs, while simultaneously measuring contractility across 24 tissues in parallel with minimal user input. This approach enables stratification of muscle phenotypes and facilitates compound safety and efficacy screening.
We present a 3D model of Duchenne muscular dystrophy that displays functional deficits consistent with in vivo disease indicators, including reduced contractile force and slowed relaxation kinetics, though beat rate remains unchanged. We show both acute and chronic effects of cardiotoxic drugs, as well as positive inotropic responses to external calcium and Isoproterenol. This highlights the utility of using EHTs to identify toxicity and derisk drug development and clinical testing outcomes. Spontaneously beating EHTs were also subjected to in situ stretching, leading to increased levels of cardiac troponin I (cTnI) in the tissue medium, indicating stretch induced injury.
These data demonstrate a first-and-only commercial platform that integrates individual, fully-customizable, well-based control of electrical stimulation across a 24-well plate of tissues to pace muscle constructs, model force-frequency, and enable exercise regimens or damage protocols. Heart organoids were stretched under load presenting a challenge for therapeutics targeting injury prevention in the myocardium. Stimulation is coupled with automated assessment of 3D muscle contraction, providing an inclusive, medium-throughput platform for studying muscle-related disorders, advancing therapeutic discovery using a modality-agnostic biosystem.
  • Luttrell, Shawn  ( Curi Bio , Seattle , Washington , United States )
  • Arefin, Ayesha  ( Curi Bio , Seattle , Washington , United States )
  • Macadangdang, Jesse  ( Curi Bio , Seattle , Washington , United States )
  • Gray, Kevin  ( Curi Bio , Seattle , Washington , United States )
  • Kharoufeh, Samir  ( Curi Bio , Seattle , Washington , United States )
  • Worthen, Christal  ( Curi Bio , Seattle , Washington , United States )
  • Luerman, Greg  ( Curi Bio , Seattle , Washington , United States )
  • Geisse, Nicholas  ( Curi Bio , Seattle , Washington , United States )
  • Author Disclosures:
    Shawn Luttrell: DO have relevant financial relationships ; Employee:Curi Bio:Active (exists now) | Ayesha Arefin: No Answer | Jesse Macadangdang: No Answer | Kevin Gray: No Answer | Samir Kharoufeh: No Answer | Christal Worthen: DO NOT have relevant financial relationships | Greg Luerman: No Answer | Nicholas Geisse: No Answer
Meeting Info:

Basic Cardiovascular Sciences

2024

Chicago, Illinois

Session Info:

Poster Session and Reception 3

Wednesday, 07/24/2024 , 04:30PM - 07:00PM

Poster Session and Reception

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