Novel Tool in Friedreich’s Ataxia Research Allows Drug Target Development

In a recent study entitled “Genome-Engineering Tools to Establish Accurate Reporter Cell Lines That Enable Identification of Therapeutic Strategies to Treat Friedreich’s Ataxia” a team of researchers described a new system that allows the identification of novel molecular pathways responsible for Friedreich’s Ataxia, as well as potential new drug targets. The study was published in the Journal of Biomolecular Screening (JBS).

Friedreich’s Ataxia patients suffer from a pattern of neuropathological defects, including muscle weakness in the arms and legs, loss of coordination, and others due to reduced expression of a mitochondrial protein, frataxin. This deficiency is a consequence of an abnormal expansion of a trinucleotide repeat in the frataxin gene, which occurs at frataxin’s first intron, i.e., a non-coding sequence within the gene. As such, therapeutics that can correct this gene defect or that increase frataxin mRNA or protein are of particular interest to Friedreich’s Ataxia patients. However, in order to develop these types of therapeutics, researchers need tools that allow them to test and identify compounds that act directly on the frataxin gene.

In this study, a research team led by Marc Bühler from the Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland and colleagues at the Genomics Institute of the Novartis Research Foundation in San Diego developed tools for genome editing that allowed the team to generate a human cell line expressing the frataxin gene fused to a luciferase reporter gene. The new cell line, termed HEK293T-FF2AP, is the first cellular model for frataxin with a luciferase reporter gene from its endogenous locus. The team performed a pilot high-throughput genomic screen using this novel cell line and discovered new negative regulators for frataxin gene expression.

The authors highlight that the tools developed in this study can enable genome editing in different cell types of any given sequence in the frataxin gene, and have the potential to become a new and crucial strategy to identify novel molecular pathways involved in the disease, as well as to assess potential drug targets.