Gene Therapy Approach in Early Tests Shows Potential to Raise Frataxin Protein Levels in Cells

A treatment approach that uses genetically engineered proteins was able to significantly increase the levels of expression of the FXN gene, which is mutated in Friedreich’s ataxia, allowing for greater frataxin protein to be produced in patients’ cells and in a mouse model of the disease.

These findings suggest a way of designing a gene therapy that might treat Friedreich’s ataxia.

The study, “Increased Frataxin Expression Induced in Friedreich Ataxia Cells by Platinum TALE-VP64s or Platinum TALE-SunTag,” was published in the journal Molecular Therapy – Nucleic Acids.

The FXN gene contains instructions to produce frataxin, an essential protein for the normal functioning of mitochondria — the powerhouses of the cell.

While frataxin is found in several cells, it is highly produced in the heart, liver, pancreas, spinal cord, and the skeletal muscles that control movement.

The most common mutation in Friedreich’s ataxia changes the FXN gene sequence in a way that impairs the initiation of gene expression — the process by which information in a gene is read to create a protein.

This mutation leads to lower production of frataxin protein, with levels as low as 4–29% of what is considered normal.

Researchers in Canada developed an approach to increase the expression of the FXN gene that uses specific proteins known as transcription activator-like effectors (TALEs).

TALEs are a class of naturally occurring DNA-binding proteins that can be easily customized to recognize specific DNA sequences. Since their discovery, researchers have used them for a wide range of applications, such as to induce specific mutations or to create artificial transcriptional activators (TA) — proteins that bind to the DNA sequence of a gene, promoting its expression and protein production.

The team used an improved version of TALEs reported to bind strongly to DNA, known as platinum TALEs.

They created a series of platinum TALE proteins fused with two naturally occurring transcriptional activators, which have been shown to recruit other transcription factors and increase the initiation of FXN gene expression and, consequently, the levels of frataxin. These fused proteins, named platinum TALE-TAs, targeted different sequences in the FXN gene.

The proteins were first tested in cells grown in the lab and derived from a Friedreich’s ataxia patient to select the ones that induced the largest increase in FXN expression.

Then, the researchers evaluated their therapeutic effects in cells from four Friedreich’s ataxia patients and in a mouse model of the disease.

Results showed that the platinum TALE-TAs increased the expression of the FXN gene both in patients’ cells and in the mice. This increase was found to improve mitochondrial activity, suggesting that this approach has the potential to alleviate disease symptoms and potentially delay disease progression.

The researchers also found that mice treated simultaneously with the two best of these platinum TALE-TAs showed even better results, with significant increases in both FXN expression and frataxin protein production. The levels of frataxin protein were significantly increased by 35-fold in the muscles, 10-fold in the heart, 3-fold in the liver, and 2-fold in the brain.

They noted that these findings strongly suggest that developing a gene therapy based on this approach could be an effective strategy to target the underlying cause of Friedreich’s ataxia, impaired FXN expression.

The team plans to conduct further tests in a different mouse model of Friedreich’s ataxia, and to improve brain delivery of the platinum TALE-TAs.