Normalizing the cardiac levels of frataxin via gene therapy or an alternative strategy could be an effective treatment for cardiac symptoms in patients with Friedreich’s ataxia (FA), as suggested by three-dimensional (3D) heart tissues made in the lab, a study suggests.
The study, “Correlation between frataxin expression and contractility revealed by in vitro Friedreich’s ataxia cardiac tissue models engineered from human pluripotent stem cells,” appeared in the journal Stem Cell Research and Therapy.
Although single-cell studies using cardiomyocytes — heart muscle cells — derived from patients’ stem cells provided valuable insights into cardiac dysfunction in FA, no such approach is able to assess complex changes at the tissue level, such as the impact on contractility. Likewise, animal studies have had limited relevance due to differences to human physiology and metabolism.
Therefore, a collaboration by Novoheart and Pfizer’s Rare Disease Research Unit is seeking to address these gaps via species-specific, functional models of FA. These models use engineered 3D cardiac tissues from stem cell-derived ventricular cardiomyocytes lacking frataxin (or FXN) — the protein produced at lower levels in FA patients.
Specifically, Novoheart’s human ventricular cardiac anisotropic sheets (which mimic the heart’s structural and functional properties) and human ventricular cardiac tissue strips — both within the company’s MyHeart Platform — were used to evaluate how reduced frataxin levels affect electrical activity and cardiac contraction, respectively.
The results revealed that tissue strips with lower frataxin levels had a 75%–80% reduction in contraction force compared with healthy controls, as well as contraction and relaxation rates that were three times slower. The FA cells also showed defects in electrical activity, such as a longer duration of action potentials (electric impulses).
The data further showed that the higher the production of frataxin, the greater the contractility. Using viral vectors to restore protein and RNA levels of frataxin also normalized cardiac cell contractility in comparison with the controls.
“Translationally, the positive correlation between FXN expression and contractility and the results of our rescue experiments underscore the potential of FXN restoration by small molecules or gene therapy as an effective therapeutic strategy for suppressing or even reversing the cardiac symptoms of [FA],” the researchers wrote.
Likewise, another study used cardiac cells from healthy donors to find that the MyHeart Platform, via cardiac tissue strips and organoid chambers — the only current human cardiac tissue model mirroring blood pumping by the heart, says the company — correctly identified nearly 90% of the compounds provided by Pfizer.
Also, the Platform showed a greater sensitivity to molecules that stimulate cardiac muscle contraction.
“These peer-reviewed publications from our ongoing collaborations with Pfizer showcase the robustness of our bioengineered heart constructs as next-generation, human-specific drug screening and disease modeling tools,” Kevin Costa, Novoheart’s chief scientific officer, said in a news release.
“Based on these exciting results, we can expand our versatile MyHeart Platform by developing additional models of human heart disease,” to develop “safer and more effective therapies for patients worldwide,” Costa added.
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