Mouse Model ‘Ideal’ for Testing Friedreich’s Ataxia Gene Therapies

The YG8-800 model captures disease features such as neurological dysfunction, heart disease

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A new mouse model called YG8-800, which accurately captures key features of Friedreich’s ataxia such as neurological dysfunction and heart disease, could be a useful tool for studying genetic therapies for the disease.

That’s according to the study, “A promising mouse model for Friedreich Ataxia progressing like human patients,” published in Behavioural Brain Research.

Mouse models are a critical tool for understanding the biological mechanisms that underlie a disease and for testing potential therapies.

Friedreich’s ataxia is mainly caused by a genetic mutation called a trinucleotide repeat in the FXN gene. In this type of mutation, three nucleotides (the “letters” of the genetic code) — a guanine followed by two adenines, or GAA — are repeated an excessive number of times, typically 600 to 900 times. This ultimately results in reduced activity of the protein frataxin.

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Several mouse models of Friedreich’s ataxia have been developed. Some early models knocked out the FXN gene in the muscles or the brain, but led to severe complications and early death.

In other models called YG8R and YG8sR, the mouse version of the FXN gene is replaced with the human version that harbors a mutation with up to 300 GAA trinucleotide repeats. While these lead to a reduction in frataxin levels, they don’t cause noteworthy symptoms in the affected mice.

Through breeding of the YG8sR strain, The Jackson Laboratory has produced a model that harbors 800 GAA trinucleotide repeats in the human FXN gene, referred to as YG8-800.

Scientists in Canada analyzed this model behaviorally and biologically to characterize it and the YG8-800 mice were compared against another mouse strain called Y47, which contains the human version of the FXN gene, but without any disease-related mutations.

Results confirmed YG8-800 mice had significantly reduced levels of frataxin protein in all their tissues, with 0.9% of the normal level of frataxin. They also showed notable hair loss and reduced body weight compared to Y47 mice.

While the general behavior of YG8-800 mice was similar to Y47 mice, the Friedreich’s ataxia model showed marked differences in motor function as time went on. For example, in measures of grip strength, the YG8-800 mice performed significantly worse than their Y47 peers starting at 20 weeks of age. In tests of coordination, YG8-800 mice showed significant deficits starting at 11 weeks.

Assessments of the mice’s hearts showed the ratio of heart size to body size was significantly enlarged in YG8-800 mice. This is indicative of a form of heart disease called cardiac hypertrophy, characterized by an enlarged heart, a serious complication of Friedreich’s ataxia.

The results suggest YG8-800 mice develop neurological and heart disease similar to what is seen in humans with Friedreich’s ataxia.

“The nervous system and heart are the most severely affected tissues in [Friedreich’s ataxia] and YG8-800 mice reflected these two characteristic of the disease. Thus, the YG8-800 mouse model appeared to represent the progressive evolution of the FRDA disease,” the researchers said, noting that since the YG8-800 model harbors a human version of the FXN gene, it may be especially well suited to studying potential gene therapies.

“This mouse model seems to perfectly represent the evolution of the disease in humans and, since it contains a human FXN gene, is the ideal model for gene therapy targeting that gene,” they wrote.

A Conversation With Rare Disease Advocates