Researchers modified two new classes of drugs, known as duplex RNAs and antisense oligonucleotides, targeted against the Frataxin (FXN) gene, which had a therapeutic effect in cells from patients with Friedreich’s ataxia.
The study titled, “Activation of Frataxin Protein Expression by Antisense Oligonucleotides Targeting the Mutant Expanded Repeat,” was published in the journal Nucleic Acid Therapeutics.
Friedreich’s Ataxia (FA) is caused by a decrease in the FXN protein levels, which occurs due to a mutation known as a trinucleotide GAA repeat that is present in the DNA sequence of the FXN gene. This mutation interferes with a process called transcription (production of RNA molecules based on the DNA sequence). However, in this case, during transcription, a structure, called an R-Loop, forms, preventing the proper process.
That makes drugs that increase the FXN protein and restore it to normal levels a potential therapy for FA. Scientists developed molecules that can recognize the expanded GAA repeat in the FXN gene, and activate transcription. These molecules include duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs).
Results from a prior study showed that dsRNAs and ASOs were able to activate expression of FXN protein at or near the levels found in healthy cells.
In this study, researchers attempted to explore the potential of dsRNAs and ASOs that are chemically modified in order to see if that would positively affect their ability to activate expression of FXN.
First, researchers showed that activation of FXN was observed in all patient-derived cell lines that were tested, which suggests these drugs might have the potential to treat many FA patients with the expanded GAA mutation.
Next, researchers showed that increased FXN protein expression was achieved by ASOs and dsRNAs that had a number of diverse chemical modifications. Some of these chemical modifications included the addition of 2’-Deoxy-2’-fluoro-beta-d-arabinonucleic acid, BNA modifications, and 2’-methoxyethyl.
An ASO, Spinraza (nusinersen), was approved at the end of 2016 for treatment of spinal muscular atrophy. Interestingly, this medicine contains a 2’-methoxyethyl chemical modification, indicating that ASOs with chemical modifications may be successfully used to treat genetic diseases.
So, the authors conclude, “Successful gene activation by different chemically modified ASOs and dsRNAs lays a firm foundation for vigorously evaluating candidates for clinical development.”