What is RNA
Ribonucleic acid (or RNA) is a nucleic acid polymer, composed of a nitrogenous base (adenine, guanine, uracil, and cytosine), a five-carbon sugar (ribose), and a phosphate group. There are three types of RNA molecules in the cells, these are messenger RNA, ribosomal RNA, and transfer RNA. Messenger RNA or mRNA is synthesized from DNA by a process called transcription and carries the information contained in a gene to the cellular machinery that produces a protein based on that information.
Synthetic RNA-based molecules
Synthetic RNA-based molecules have increasingly been recognized as potential therapeutic agents and several of them are currently under clinical development to treat different conditions. Two such RNA-based molecules are duplex RNAs and locked nucleic acid (LNA) oligonucleotides, which are designed to bind to complementary sequences.
The sugar molecule in the LNA oligonucleotides is locked in a ring structure. This increases the molecule’s affinity, sensitivity, and specificity for complementary sequences; while duplex RNAs bind to complementary sequences with the assistance of specific cellular proteins, LNA oligos do not need any such proteins.
RNA-based treatment approaches in FA
Friedreich’s ataxia is a genetic neuromuscular disorder caused by an abnormal expansion of the trinucleotide GAA (guanine-adenine-adenine) repeat within the FXN gene, which leads to reduced transcription (conversion of DNA into RNA) and thus, low levels of frataxin protein being produced. Frataxin plays an essential role in the mitochondria, which are the energy producing centers of the cells.
The mechanism by which GAA-repeat expansion silences transcription is suggested to be via an ‘R-loop’, which is formed when the expanded GAA repeat within the FXN mRNA binds to the complementary DNA sequence. The formation of this R-loop may then prevent further transcription, reducing the levels of frataxin protein being produced. Since only the protein levels are reduced without any change in the protein sequence, FA could be treated by increasing frataxin expression by preventing the RNA-DNA binding.
Both duplex RNAs and LNAs share a common feature – the ability to block GAA repeats within the newly formed FXN mRNA. Scientists have shown using patient derived cells that synthetic nucleic acids complementary to the GAA repeat – anti-GAA duplex RNAs or single-stranded LNA oligonucleotides – are able to bind to the expanded RNA, blocking R-loop formation and resulting in the activation of transcription. These synthetic molecules increased the levels of frataxin protein to levels similar to normal cells.
RNA-based treatment approaches are very much in their infancy and far from being ready to be used in the clinic for the treatment of FA. Encouragingly, ProQR, a company that develops RNA-based therapies for severe genetic diseases, has initiated an innovative program where they are working on QRX-604, a molecule that aims to increase frataxin protein levels in people with FA.
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