New FA mouse model may aid research, therapy development

Mice house largest reported number of GAA repeats in FXN gene

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A new mouse model of Friedreich’s ataxia (FA), designed to better reflect a more severe disease course, could help researchers study the disease’s mechanisms and develop new therapies.

The mice, which reportedly house the largest number of GAA repeats in the FXN gene of any existing model — about 800-900 of them — exhibited cellular and behavioral features consistent with FA, including motor problems, genetic changes, and reduced levels of the frataxin protein.

The new model was described in “A new FRDA mouse model [ Fxn null:YG8s(GAA) > 800] with more than 800 GAA repeats,” which was published in Frontiers in Neuroscience.

In FA, mutations in FXN lead to the insufficient production of the frataxin protein, which plays a role in the function of mitochondria, cells’ energy production centers.

There’s a region of the gene where a trio of nucleotides — the building blocks of DNA — are normally repeated about 5 to 33 times. In FA, the trio, consisting of a guanine (G) and two adenines (A), is repeated more than normal — usually hundreds of times.

The number of repeats is associated with age of disease onset, its severity and how quickly it progresses, with a greater repeat number generally linked to earlier, more severe, and faster progressing disease.

Therapies for FA are lacking. Last month, Skyclarys (omaveloxolone) became the first approved treatment, but no single therapy will work for every patient.

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To develop new therapeutic options, optimized preclinical models of the disease are needed. A good model reflects the disease’s underlying cause and is marked by the same cellular and behavioral changes seen in the human condition.

Previous mouse models developed by the research team could partially do this. These mice were genetically engineered to contain the human version of the FXN gene, with different versions housing up to about 300 GAA repeats. They had reduced frataxin levels and signs of mild, late-onset FA.

Most patients have more than 300 repeats, however, according to the researchers, who noted the importance of accurate modeling since the number of repeats influences disease severity.

They developed a new mouse model, called YG8JR, which was derived from their previous model. It’s expected to have the largest GAA repeat size of all currently available models.

In the study, the researchers compared these mice to healthy mice housing the human FXN gene with a normal number of GAA repeats.

YG8JR mice were found to have decreased body weight than their healthy counterparts, as well as notable motor deficits across different tests that started early and worsened with time. These impairments were stronger and occurred earlier compared to models with fewer GAA repeats, the researchers said.

The FA mice were found to have about 820-900 GAA repeats, a number that that seemed to change with each new generation. Correspondingly, they had reduced levels of the frataxin protein — about a 21% decrease compared with healthy mice. That reduction is similar to observations in FA patients, according to the researchers.

A number of epigenetic changes to FXN were also observed in the cerebellum, a brain region implicated in the motor problems that mark FA. Epigenetics refers to chemical modifications that don’t alter a gene’s sequence, or nucleotide composition, but do affect how genes are read, and thus, their activity. These types of changes are also observed in FA patients.

Frataxin loss in FA has been associated with the dysregulation of iron-sulfur protein clusters and oxidative stress, a type of cell damage implicated in FA. The YG8JR mice exhibited significantly lower activity of aconitase, an enzyme with an iron-sulfur cluster, in the cerebellum.

“As a whole, we report that the YG8JR mouse model exhibits progressive [FA]-like pathology with earlier onset, as compared to the previously described … models with lower GAA repeat expansions,” the researchers wrote. “The YG8JR mice can be a useful model for the investigation of FRDA disease mechanisms and therapy.”