Promising Gene Therapy for Friedreich’s Ataxia Based on Frataxin Expression

A team led by researchers at the Universidad Autónoma de Madrid in Spain recently published new data on a gene therapy for Friedreich’s ataxia based on the expression of the human frataxin gene from artificial systems. The study is entitled “Delivery of the 135 kb human frataxin genomic DNA locus gives rise to different frataxin isoforms” and was published in the journal Genomics.

Friedreich’s ataxia is a rare inherited neurodegenerative disease characterized by progressive damage of the nervous system with degeneration of the spinal cord and peripheral nerves that leads to muscle weakness, sensory loss, balance deficits and lack of voluntary coordination of muscle movements. The disease is caused by a mutation in a gene called frataxin (FXN) that leads to a defective expression of the frataxin protein. Disease onset is usually during childhood or adolescence and the disorder leads to progressive disability, dependence on a wheelchair and reduced life expectancy. Currently, there is no effective approved treatment for the disease.

The frataxin protein is found in the mitochondria, small cellular organelles considered the “powerhouse” of cells. Frataxin is synthesized as a precursor form that is processed by mitochondrial processing peptidase to generate the mature form of the protein. It has been reported that different frataxin isoforms can be formed due to alternative gene expression mechanisms.

Vectors carrying frataxin DNA (like viral vectors) have been shown to rescue, to some extent, the disease phenotype in cells derived from Friedreich’s ataxia patients and in mouse models. The research team in this study has previously reported the use of high-capacity herpes simplex virus type 1 (HSV-1) amplicon vectors carrying the entire FXN genomic locus (iBAC-FXN) as a successful gene-delivery system that is capable of inducing a physiological level of frataxin expression, a long-term persistence of the protein and functional restoration of the normal conditions in cells from Friedreich’s ataxia patients and in mice models.

In this study, the team used the same iBAC-FXN system to analyze the expression of different frataxin isoforms both in cultured cells and after intracranial injection into mice. Researchers found that FXN expression from the iBAC-FXN yielded, in both cultured cells and in mice, all the different frataxin isoforms which have been previously described.

The team concluded that gene therapy based on HSV-1 vectors containing the entire genomic loci of the frataxin gene might be a promising alternative therapeutic strategy for Friedreich’s ataxia. The team suggests that the proper expression of all the frataxin isoforms might be crucial for a full restoration of the frataxin expression and therefore, for the recovery of the neuronal function.