RNA stands for ribonucleic acid and it is a similar molecule to DNA. There are different types of RNA but for the purpose of explaining RNA as a target for therapies, we are going to describe messenger RNA (mRNA). mRNA is produced from DNA, in a process called transcription, and it forms a strand of letters that are a condensed copy of the gene containing the instructions to make a protein. mRNA is read by the protein-making machinery in our cells, called ribosomes, to produce a protein in a process called translation.
When the RNA is transcribed from a gene which holds a genetic mutation, this can also be found in the RNA. This means that the mutation is passed on when making the protein, and if the protein is defective or not produced, then it will lead to disease in the cell and tissue. Hence, RNA therapy is designed to correct the mutation in the RNA of the patient, which means that the mutation is not passed on, and correct healthy functioning protein can be made.
RNA therapy is a form of genetic therapy also called antisense oligonucleotides, or AON or ASO treatment. It consists of a short strand of synthetic RNA letters that match the RNA they are targeting. When they find the RNA in the cell, they bind to it and prevent the mutation from having an effect. Unlike gene therapy and gene editing, which delivers new DNA or makes permanent changes to it respectively, the effect of RNA therapy is more short-lived. These drugs are delivered to the eye through an intravitreal injection.
1) Leber congenital amaurosis caused by a CEP290 gene mutation
Sepofarsen (formerly named QR-110) is an RNA therapy developed to counter a specific common mutation in the CEP290 gene (known as c.2991+1655A>G, p.Cys998X). This drug has been evaluated in phase 1/2 clinical trials and is well-tolerated. An improvement in vision was also observed, hence a larger phase 2/3 clinical trial has begun to assess the effect further (ILLUMINATE, NCT 03913143).
2) Usher syndrome caused by mutations in exon 13 of USH2A
QR-421a is an RNA therapy for patients with retinitis pigmentosa (RP) and Usher syndrome due to mutations in a specific part of the USH2A gene (which is made up of 72 subunits or exons—letters that code for a protein). Although mutations are found across the whole gene, the most prevalent mutations for RP and Usher syndrome are located in exon 13, and this is the region targeted by this QR-421a. It removes exon 13 from the mRNA and subsequently leads to production of a shorter but functional USH2A protein. QR-421a is currently being evaluated in a phase 1/2 clinical trial (STELLAR, NCT 03780257).
3) Retinitis pigmentosa caused by a RHO gene mutation
One form of RP is caused by a common mutation in the rhodopsin (RHO) gene, known as c.68C>A or p.P23H. The p.P23H mutation produces a mutated rhodopsin protein, which over time blocks the function of the normal rhodopsin protein and causes toxic damage to the photoreceptors in the retina.
QR-1123 drug works by binding to the mutated RNA and removes it from the cell by breaking it down safely. This allows the normal protein to perform its function in the retina and preventing further toxicity. This drug is currently being evaluated in a phase1/2 clinical trial (AURORA, NCT 04123626).
So far, these drugs have been well tolerated by trial participants, but the trials in Usher syndrome and RP are still in their early phases of safety evaluation. Each drug is specific to a mutation and there may be off-target effects (affecting other cells in the body with similar RNA letters as the synthetic RNA) that have not been detected yet. As these trials progress we will learn more, but the preliminary results are promising.
These RNA therapies target either a specific mutation, which may be particularly common, or mutations in a specific location of a gene. Therefore, these therapies do not treat all patients with the diagnosis. This is one of the reasons why genetic testing is important for individuals affected by inherited conditions as without having a genetic diagnosis, you may not be able to access these new therapies.
- Dulla K, Aguila M, Lane A, et al. Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models. Mol Ther Nucleic Acids. Sep 7 2018;12:730-740. doi:10.1016/j.omtn.2018.07.010
- Cideciyan AV, Jacobson SG, Drack AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med. Feb 2019;25(2):225-228. doi:10.1038/s41591-018-0295-0