Inhibition of FAST-1 Molecule May Have Therapeutic Potential in Friedreich’s Ataxia, Study Confirms

Inhibition of FAST-1 Molecule May Have Therapeutic Potential in Friedreich’s Ataxia, Study Confirms

A naturally produced RNA molecule called FAST-1 can prevent the readout of the FXN gene and, consequently, production of the frataxin protein, contributing to the development of Friedreich’s ataxia, researchers suggest.

This finding was reported in a study published in the journal Scientific Reports and supports the hypothesis that inhibition of FAST-1 may hold therapeutic potential for the rare disease. The study is titled “FAST-1 antisense RNA epigenetically alters FXN expression.”

Friedreich’s ataxia is a genetic disease characterized by impaired production of frataxin protein because of abnormal GAA sequence repeats in the FXN gene.

Several studies have also suggested that, besides this genetic alteration, factors such as abnormal silencing of the gene because of deregulated epigenetic mechanisms could have an important role in Friedreich’s ataxia development.

Epigenetic alterations occur when the DNA sequence itself is not altered, but epigenetic marks are added to it. These switch the gene on or off, inducing either its activation or repression (production of the protein or not).

In 2009, a research team discovered that a naturally produced RNA molecule called FXN Antisense Transcript-1, or FAST-1, was increased in patients with Friedreich’s ataxia. Importantly, this molecule would prevent the normal readout of FXN gene and prevent normal production of frataxin protein.

A team at Brunel University London further explored the role of this FAST-1 molecule in the underlying molecular mechanisms of Friedreich’s ataxia.

They genetically modified experimental cell models to force the production of FAST-1. This led to a reduction of FXN gene expression levels (42-47% of the normal cells’ levels) and of frataxin protein (40-58% compared with unaltered cells). Importantly, the inhibitory effect of FAST-1 was found to be dependent on its level in cells.

Further experiments showed that upon increasing the levels of FAST-1, the cells started to show altered patterns on epigenetic markers in the FXN gene. The amount of gene-silencing epigenetic markers increased from 8% in control cells up to 76-79% in the presence of high FAST-1 levels.

Next, the team genetically inhibited FAST-1 in cells collected from people diagnosed with Friedreich’s ataxia. With a reduction of about 63% in FAST-1 levels, researchers could increase the amount of FXN gene expression 1.5-fold, with no impact on healthy control cells.

Also, aconitase enzyme activity — a readout measure of functional frataxin — increased from 49% to 195% compared with control cells upon inhibition of FAST-1.

Supported by these findings, the team expressed the belief that “inhibition of FAST-1 may be an approach for Friedreich’s ataxia therapy.”

“Considering the nature of natural antisense transcripts (NATs) and the fact that many currently available drugs would not affect the activity of non-coding RNA molecules, developing new methods to disrupt the function of NATs seems necessary,” they said.

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