Researchers have successfully corrected a mutated frataxin gene that leads to reduced production of the frataxin (FTX) protein and development of disease in mice, according to new research.
This achievement provides new insight into laboratory methods to study the disease and supports the therapeutic potential of gene editing techniques to treat patients with Friedreich’s ataxia (FRDA) in the future.
The study, “Deletion Of The GAA Repeats From The Human Frataxin Gene Using The CRISPR-Cas9 System In YG8R-derived Cells And Mouse Models Of Friedreich Ataxia,” was published in the journal Gene Therapy.
Friedreich’s ataxia is an incurable pediatric neurodegenerative disease caused by a mutation in the frataxin gene, called a GAA repeat expansion, which impairs the normal expression of the FTX protein. This in turn limits the production of iron-sulfur proteins in the mitochondria, the cell’s energy storehouse, causing a decline in energy production, oxidative damage, altered iron metabolism, and general mitochondrial dysfunction.
In recent years, researchers have developed gene editing techniques that allow them to repair, replace, or modify specific genes. This ability has great therapeutic potential for diseases caused by gene mutations, such as Friedreich’s ataxia.
“As a monogenic disease, FRDA is a good pathology candidate for gene therapy, thus some research projects are trying to increase the frataxin protein level in FRDA cells and in mouse models using gene therapy approaches,” the researchers wrote.
Researchers used CRISPR-Cas9, a system that uses specialized proteins to precisely target a given DNA segment to remove the mutated GAA expansion from the DNA of two mouse models carrying copies of the human frataxin gene, known as YG8R and YG8sR mice. The YG8sR model presents more severe symptoms than the original mouse model, including significant behavioral deficits. They also performed the technique in cell cultures derived from these animals.
Results showed this method successfully corrected the mutated portion of the gene both in mice and cell cultures, thereby restoring the proper expression of the frataxin gene and production of the FTX protein.
Researchers also noted that the YG8sR mice seem to be a better and more suitable model to study the potential therapeutic effects of correcting the mutated frataxin gene using CRISPR-Cas9 system.
According to the authors, more studies using living animals are necessary “to verify whether the GAA edition increases the FXN protein expression enough to reduce or abrogate the symptoms associated to the Friedreich’s ataxia.”
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