RNA editing promises to go where DNA editing can’t Premium

Wave Life Sciences pioneers RNA editing for genetic conditions, sparking a new era in precision medicine.

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.