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On October 16, a biotechnology company in Massachusetts in the U.S. named Wave Life Sciences made headlines for becoming the first company to treat a genetic condition by editing RNA at the clinical level. But for all that this is a breakthrough, scientists had anticipated it.
The role of RNA in a function called RNA interference — where small RNA molecules keep a gene from being expressed — has been essential for the success of CRISPR-Cas9 gene-editing. The rapid development of mRNA vaccines during the COVID-19 pandemic exemplified the complex as well as vital role RNAs play beyond gene expression and regulation. Now, at the dawn of a new era in precision medicine, RNA editing has made a pitch to be at the forefront.
Cells synthesise messenger RNA (mRNA) using instructions in DNA and then ‘read’ instructions from the mRNA to make functional proteins. During this process of transcription, the cell may make mistakes in the mRNA’s sequence and based on it produce faulty proteins. Many of these proteins have been known to cause debilitating disorders. RNA editing allows scientists to fix mistakes in the mRNA after the cell has synthesised it but before the cell reads it to make the proteins.
One technique involves a group of enzymes called adenosine deaminase acting on RNA (ADAR). Adenosine is one of the building blocks of RNA. ADAR works by converting some of the adenosine blocks in mRNA to another molecule called inosine. This is useful because inosine mimics the function of a different RNA building block called guanosine. Because guanosine-like function is found where adenosine is supposed to be, the cell detects a mistake and proceeds to correct it, in the process restoring the mRNA’s original function. And then the cell makes normal proteins.
Scientists took advantage of ADAR’s effects to pair it with a guide RNA (or gRNA): the gRNA guides ADAR to a specific part of the mRNA, where the ADAR works its magic. They expect a variety of serious genetic conditions can be treated using such site-specific RNA editing.
Wave Life Sciences used RNA editing to treat α-1 antitrypsin deficiency (AATD), an inherited disorder. In patients suffering from AATD, levels of the protein α-1 antitrypsin build up and affect the liver and the lungs. People with AATD affecting the lungs currently go through weekly intravenous therapy for relief; among people where AATD has affected the liver, a liver transplant is the sole treatment option.
In its therapy, dubbed WVE-006, the company used a gRNA to lead ADAR enzymes to specific single-point mutations in the mRNA sequence of the SERPINA1 gene, which contains the instructions for cells to make α-1 antitrypsin. A single-point mutation occurs when a single building block of the mRNA is wrong. Once at the target, the ADAR enzymes fix the mRNA and the cells produce α-1 antitrypsin at normal levels.
Wave Life Sciences is planning to extend its RNA editing technology to treat Huntington’s disease, Duchenne muscular dystrophy, and obesity. The first two and some forms of obesity are associated with single-point mutations.
Some other companies using ADAR enzymes to perform RNA editing are Korro Bio for AATD and Parkinson’s disease; ProQr Therapeutics for heart disease and bile acid build-up in the liver; and Shape Therapeutics for neurological conditions. They use different guides, RNA types, and delivery mechanisms, however.
Researchers are also extending RNA editing to make changes in the exon. mRNA is made up of portions called introns and exons: exons eventually code for a protein whereas the introns are non-coding parts and are removed from the RNA before it’s used to make a protein.
A company called Ascidian Therapeutic is testing its candidate to treat ABCA4 retinopathy. Several mutations in the ABCA4 gene lead to different levels of protein expression and disease severity. The ABCA4 gene is large, so standard gene replacement therapy is not feasible; instead, RNA editing is expected to be able to offer a way out. The candidate started clinical trials in January 2024 with a fast-track designation granted by the U.S. drug regulator.
The same regulator permitted South Korean company Rznomics to conduct trials in the U.S. for its candidate to treat forms of liver cancer. In South Korea, this candidate has already proceeded to phase I and II trials. It works by regulating the production of human telomerase reverse transcriptase, a protein that affects tumour formation.
RNA editing has some advantages over DNA editing, especially on safety and flexibility. DNA editing makes permanent changes to a person’s genome and sometimes this can lead to irreversible errors. On the other hand, RNA editing makes temporary changes, allowing the effects of the edits to fade over time. In a clinic, this means a doctor can stop the therapy if a problem arises and mitigate long-term risk.
Second, CRISPR-Cas9 and other DNA editing tools require proteins acquired from certain bacteria to perform the cutting function, but these proteins can elicit undesirable immune reactions in some cases. RNA editing relies on ADAR enzymes, which already occur in the human body and thus present a lower risk of allergic reactions. This is useful for people who require repeated treatment and/or who have immune sensitivities.
A big challenge in RNA editing is its specificity. ADARs can perform adenosine-inosine changes in both targeted and non-targeted parts of mRNA, or skip the targeted parts altogether. When ADARs don’t align with the adenosine of interest, potentially serious side-effects could arise. Scientists are currently trying to improve the accuracy of gRNA by incorporating mechanisms that shield non-targeted parts of the mRNA.
Another challenge is the transient nature of RNA editing: this is also its strength, but individuals will need to be treated repeatedly to sustain the therapy’s effects.
Third, current methods to deliver the gRNA-ADAR complex use lipid nanoparticles. Researchers used them to great success to make mRNA vaccines to treat COVID-19 and the adeno-associated virus (AAV) vectors used in gene editing. But both these methods have a limited carrying capacity, meaning they can’t transport large molecules very well.
RNA editing is in its nascent stage, yet there are already at least 11 biotechnology companies worldwide developing RNA editing methods for a range of diseases. Their efforts have elicited interest from large pharmaceutical firms including Eli Lilly, Roche, and Novo Nordisk.
As research and clinical trials advance in the field of RNA editing, it seems like only a matter of time before RNA editing becomes a fixture of the gene-editing toolkit in clinical practice.
Manjeera Gowravaram has a PhD in RNA biochemistry and works as a freelance science writer.
Published - November 07, 2024 05:30 am IST