Removal of the genetic defect that causes Friedreich’s ataxia (FA) in heart cells derived from a patient with heart disease associated with FA reversed the cells’ abnormal molecular profile, a study shows.

This gene-editing strategy could be a useful tool for regenerative medicine aimed at treating heart defects associated with the condition.

The study, “Excision of the expanded GAA repeats corrects cardiomyopathy phenotypes of iPSC-derived Friedreich’s ataxia cardiomyocytes,” was published in the journal Stem Cell Research.

Friedreich’s ataxia is a rare neurodegenerative disorder caused by excessive repeats of a portion of DNA, called GAA triplets, within the FXN gene. This gene contains instructions to produce frataxin, an essential protein for the normal functioning of mitochondria — the powerhouses of the cell.

The expansion of the GAA triplet-repeats significantly decreases the production of frataxin, causing mitochondrial dysfunction and impaired energy production in several organs, including the heart.

Hypertrophic cardiomyopathy — or thickening of the walls of the heart, making it harder to pump blood to the rest of the body — is the most common heart abnormality seen in people with Friedreich’s ataxia and the leading cause of death in more than half of these patients.

Researchers have faced challenges in the development of an animal model that mimics the heart condition associated with Friedreich’s ataxia, because the usual genetic approaches involve full removal of the FXN gene, and not the reduction of frataxin production.

The production of cardiomyocytes (heart cells) from induced pluripotent stem cells (iPSCs) — stem cells derived from differentiated cells that can generate virtually any cell type in the body — of Friedreich’s ataxia patients has the potential to be a successful cellular model of heart complications associated with this disease.

Researchers have now used this strategy to assess the molecular changes in heart cells of Friedreich’s ataxia patients, and to evaluate whether removal of the excessive GAA repeats within the FXN gene in these patient-derived heart cells could revert those molecular changes.

They compared the features of heart cells generated from iPSCs of two healthy individuals and those of an FA patient with diagnosed heart disease. The analysis also included heart cells generated from iPSCs of the same patient that were genetically modified to lack the expansion of GAA repeats in a single FXNgene copy.

The results showed that patient-derived heart cells had significantly lower levels of frataxin and an increased accumulation of lipid droplets — storage organelles involved in lipid (fatty molecules) and energy balance — than those derived from healthy individuals.

Furthermore, the gene expression profile of patient-derived heart cells was comparable to that of two distinct cellular models of hypertrophic cardiomyopathy. The gene expression profile is the combination of all the genes in a cell or tissue that are producing messenger RNA, the intermediate molecule that contains the instructions to produce a protein.

Patient-derived heart cells without the expanded GAA repeats in the FXN gene showed a significant increase in frataxin levels, a reduction in lipid droplet accumulation, and a reversal of the gene expression profile of Friedreich’s ataxia’s heart cells.

The correction of the defective FXN gene in patient-derived heart cells placed them closer to unaffected heart cells in terms of frataxin production, lipid metabolism, and gene expression profile.

“The iPSC-derived [Friedreich’s ataxia] cardiomyocytes exhibit various molecular defects characteristic for cellular models of cardiomyopathy [heart disease] that can be corrected by genome editing of the expanded GAA repeats,” the researchers said.

They noted that “in the later stages of the disease, after cell death becomes apparent and damage irreversible, cell replacement therapy may represent a stronger avenue for treatment … [and] results of these studies serve as a proof of concept for potential regenerative medicine approaches to treat the cardiac [heart] defect in FRDA.”

The team emphasized that this cellular model may also be used to identify new biomarkers of heart disease in these patients and to evaluate new potential therapies for heart disease in people with Friedreich’s ataxia.