Researchers Make New iPSC Models of Friedreich’s Ataxia

Marisa Wexler MS avatar

by Marisa Wexler MS |

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A team of scientists at Koc University in Turkey has created three new cell models of Friedreich’s ataxia (FA) derived from patients with repeat expansions in their FXN gene.

The models “will facilitate studies to understand molecular mechanisms related to FRDA [Friedreich’s ataxia] pathology [disease processes] as well as therapeutic investigations such as drug screening or gene editing,” the researchers wrote.

The models were described in the paper, “Generation of transgene-free iPSC lines from three patients with Friedreich’s ataxia (FRDA) carrying GAA triplet expansions in the first intron of FXN gene,” published in Stem Cell Research.

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FA is caused by mutations in the gene FXN, which provides instructions for making a protein called frataxin. The most common type of disease-causing mutation is a trinucleotide repeat expansion, when a particular sequence in the FXN gene — one guanine (G) and two adenines (A), which are two of the four building blocks of DNA — is repeated an abnormally high number of times.

The Koc team created three induced pluripotent stem cell (iPSC) lines from people with FA who have a GAA trinucleotide repeat in the FXN gene. iPSCs are a type of stem cell, meaning they are able to grow and differentiate into other types of cells in the body. However, iPSCs are stem cells that are “reverse engineered” from mature cells, such as those in the skin or blood.

Here, the researchers collected a type of skin cell, called fibroblasts, from three unrelated individuals with FA. They then used established genetic manipulation techniques to “program” the fibroblasts into iPSCs.

With this approach, the researchers created three iPSC lines that had the same FA-causing GAA trinucleotide repeat mutations as the three patients.

A battery of analyses demonstrated that the iPSCs were behaving as expected — that is, they had a “stem-like” appearance, as well as increased expression of genes related to stem cell behaviors. Experiments done in mice demonstrated that the cells are able to grow and differentiate into many other lineages of cells.

An advantage of using iPSCs is that, given the right chemical cues, they can be programmed to grow and differentiate into any other kind of cell that researchers want to study — a liver cell, a muscle cell, a brain cell, etc. As such, the researchers are hopeful these new models may be useful for studying FA, both to understand the underlying mechanisms that drive the disease and to test potential treatments.