As therapies for Friedreich’s ataxia seek to increase the amount of frataxin, whose shortage underlies the disease, scientists conducting an in vitro study warn that levels of the protein must be tightly regulated because overproduction may result in detrimental effects.
The study, “Adding a temporal dimension to the study of Friedreich’s ataxia: the effect of frataxin overexpression in a human cell model,” was published in the journal Disease Models & Mechanisms.
Increasing the levels of frataxin — a mitochondrial protein — is the goal of many of the therapies currently being investigated for the disease, including those using gene therapy with the CRISPR-Cas9 technology.
However, a key step in Friedreich’s ataxia therapies is to understand which levels of frataxin are necessary for a healthy individual.
Studies using animal models have produced conflicting results. Some studies showed that higher-than-normal levels (overexpression) of frataxin lead to positive results, especially by protecting the cells against oxidative stress — a condition that damages tissues and organs.
But other studies have reported that increasing frataxin levels can actually promote this form of stress.
One study using the fruit fly, called Drosophila, as a model organism reported that a systemic (meaning in all cells of the body) increase in frataxin levels impaired the flies’ normal embryonic development of muscles and the peripheral nervous system.
Now, a team of European researchers used the CRISPR-Cas9 technology to modify a mammalian cell line. They first deleted the natural frataxin gene, called FXN, from the cells and they replaced it with an inducible FXN gene.
With this strategy they were able to “turn on” the gene and induce the accumulation of frataxin, but they can also see how the cells recover from this increase when the gene is turned off.
The results showed that the higher production of frataxin had no beneficial advantage to mitochondrial function and, on the contrary, affected the metabolism of cells. Specifically, there was a significant increase of oxidative stress and changes in the normal levels of iron in cells.
“These cellular alterations are similar to those observed when the gene is partially silenced, as it occurs in Friedreich’s ataxia patients,” researchers wrote.
“Our data suggest that the levels of frataxin must be tightly regulated and fine-tuned,” they added, with imbalances “leading to oxidative stress and toxicity.”
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