Researchers Create Fabry Heart Disease Model in a Culture Dish

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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Japanese researchers have used stem cells from Fabry patients to create an innovative laboratory model that mimics heart disease in a culture dish.

They are now planning to use this in vitro disease model as a screening system to promote drug discovery and to improve the prognosis of patients with Fabry cardiomyopathy (heart disease).

The study, “Generation of Fabry cardiomyopathy model for drug screening using induced pluripotent stem cell-derived cardiomyocytes from a female Fabry patient,” was published in the Journal of Molecular and Cellular Cardiology.

Fabry disease is a a rare genetic disorder caused by mutations in the GLA gene — located in the X chromosome — that encodes for an enzyme called alpha-galactosidase A (GLA). These mutations usually affect the function of GLA, leading to the accumulation of a type of fat called globotriaosylceramide (Gb3) in several organs, including the heart.

Heart disease is the most frequent cause of death among Fabry patients. Fabry cardiomyopathy usually emerges as left ventricular hypertrophy (LVH) — abnormal thickness of the left ventricular wall of the heart — and develops into heart failure, myocardial infarction and life-threatening arrhythmias. Unfortunately, current treatments for the condition have limited effectiveness.

In this study, researchers created and validated an innovative Fabry cardiomyopathy model in a culture dish intended to facilitate drug screening to speed drug discovery and to improve the prognosis of Fabry patients suffering from cardiomyopathy.

They used pluripotent stem cells (iPSCs) — fully matured cells that are reprogrammed back to a stem cell state, where they are able to grow into any type of cell — from a female Fabry patient and her son.

iPSCs lacking normal GLA activity were used as a Fabry disease model, while iPSCs that still retained normal GLA activity were used as an experimental control.

Then, researchers generated heart muscle cells (cardiomyocytes) from iPSCs (iPS-CMs) to study the effects of Fabry disease on cells from the heart.

These iPS-CMs derived from iPSCs lacking normal GLA activity had an accumulation of Gb3, a hallmark of Fabry disease.

In addition, the team also found the expression levels of atrial natriuretic peptide (ANP) — a peptide that is highly expressed when the heart is under high pressure and becomes enlarged (hypertrophy) — were abnormally increased in iPS-CMs from the Fabry model, while cell surface area was decreased. This indicated that these Fabry iPS-CMs are already undergoing molecular changes associated with heart disease.

“In contrast to the lack of morphological hypertrophy, we observed that the expression of ANP was significantly increased in Fabry iPS-CMs. This suggests that the increased expression of ANP precedes morphological hypertrophy and may suggest that the treatment against Fabry disease should be started before apparent LVH [left ventricular hypertrophy] is observed,” the authors wrote.

Researchers also developed an algorithm to detect and distinguish Gb3 accumulation inside cells they are hoping could be used for high-throughput drug screening.

“[W]e developed a high-content screening assay that detects lysosomal Gb3 accumulation in iPS-CMs, requires simple procedures and can be easily developed into high-throughput screening. ‘Black-box’ screening using our system may lead to the identification of previously unrecognized mechanisms and therapeutic targets of Fabry cardiomyopathy,” they concluded.