Two small molecules were shown to increase the mRNA and protein levels of frataxin (FXN) in animal models of Friedreich’s ataxia. According to a report published at Neuropharmacology, these compounds could have therapeutic potential to treat FXN deficits in Friedreich’s ataxia (FA).
Friedreich’s ataxia is caused by reduced levels of the mitochondrial protein FXN. Although the functions of this protein are not fully understood, studies have shown that it is involved in several mechanisms of DNA repair and iron metabolism. A reduction of FXN production was shown to be associated with a reduced number of mitochondria – the “powerhouse” of cells – which could in part explain the manifestations of FA.
Finding ways to increase levels of FXN in these patients has been a major focus of therapeutic strategy for this disease. Protein replacement therapy, modulators of gene expression, and gene therapies have all been tested toward this end. Unfortunately, these methods have not been effective in improving all symptoms of Friedreich’s ataxia.
Erythropoietin (EPO) is a protein that is mainly known as regulator of red blood cell production. More recent studies have revealed that it can also act as a potent tissue-protective, anti-apoptotic (apoptosis refers to programmed cell death), and anti-inflammatory protein.
Lab-produced human EPO (rhEPO) has been shown to increase the levels of FXN in several human cells in experimental settings and early clinical studies. But the therapeutic potential of EPO has not yet been fully explored in Friedreich’s ataxia models.
In the study titled, “Erythropoietin and small molecule agonists of the tissue-protective erythropoietin receptor increase FXN expression in neuronal cells in vitro and in Fxn-deficient KIKO mice in vivo,” researchers from STATegics and the Université Libre de Bruxelles evaluated the therapeutic potential of two small molecules, STS-E412 and STS-E424, for the treatment of Friedreich’s ataxia.
These two investigative therapies were specifically engineered to activate the tissue-protective EPO receptor.
The team of researchers tested STS-E412 and STS-E424 in mouse and human neuron-like cells and observed a two-fold increase in the expression of FNX. This positive effect also was observed in blood cells collected from patients with Friedreich’s ataxia.
But the effect of these small molecules was not restricted to the protein. The researchers also observed increased levels of the mRNA (the transcript of the gene that results in a protein) of FXN in cells exposed to STS-E412 and STS-E424.
This finding suggests that the activity of these therapy candidates may also affect FXN gene expression and not only protein stability. The observed mRNA effect was similar to that found in treatment with HDAC inhibitors, a potential therapy for Friedreich’s ataxia currently under investigation.
The researchers confirmed these findings in FXN-deficient mice. Upon treatment with STS-E412 and STS-E424, the animals presented increased levels of FXN in the heart similar to rhEPO. In addition, these small molecules could also increase the levels of FXN in the animals’ brains, which rhEPO protein failed to achieve.
“The results described here illustrate that these small molecules, like rhEPO, increase FXN mRNA and protein in vitro and in a rodent model of FA,” the authors wrote. “Significantly, their small size and consequent tissue-permeability and ability to cross the blood-brain barrier to increase FXN protein in brain, broad cytoprotective activity, lack of erythropoietic activity and oral bioavailability suggest that STS-E412 and STS-E424 may have therapeutic potential in the treatment of FA,” they added.