Alpha-1-antitrypsin disease (AATD) is caused by mutations in the SERPINA1 gene coding for alpha-1-antitrypsin (AAT).  There are an estimated 100000 alpha-1 patients in the US alone, making it a rare, but not ultra-rare disease. Correcting these mutations, replacing AAT through gene therapy, or inhibiting the particularly pathogenic Z-allele is subject to the efforts of a number of nucleic ..read more

There was a time, not that long ago, when 1-3% ADAR editing rates in tissue culture cells were typically reported in the field.  The hope then was that with further chemical optimization, editing rates could be increased high enough to have a clinically relevant impact in the setting of a gain-of-function approach.  Mathematically speaking, go from nothing to something is an immeasurable relative ..read more

Today, pure-play ADAR Editing Korro Bio announced that it will reverse merge into biotech shell Frequency Therapeutics (current ticker: FREQ, to be changed to KRRO).  It will thus become the 3rd publicly traded RNA Editing company following ProQR (pure-play) and Wave Life Sciences, the latter entertaining a broader mix of oligonucleotide therapeutics modalities (ADAR editing, exon skipping, RNAi ..read more

Roche has shown interest in RNA Editing through its 2021 partnership with Shape Therapeutics.  The goal of this partnership was to use Shape’s AAV-delivered, DNA-directed RNA editing nucleic acids for neuroscience and rare disease applications. Readers of this blog will know that I have not been a great fan of DNA-directed approaches to ADAR editing, not least because the expressed editing RNAs ..read more

In the span of a day, RNAi Therapeutics have gone from a mechanism widely viewed as being constrained to the liver only, to a major therapeutic modality for many targets and indications in a variety of tissues.  Due to the demonstrations in the liver, lung (yesterday), and today the central nervous system to potently and specifically knock down genes with infrequent dosing, RNAi will play a ..read more

With every new oligonucleotide therapeutics modality that feeds into an endogenous cellular mechanism comes uncertainty as to whether the mechanism is sufficiently robust to be of therapeutic utility.  This is especially true for RNA Editing as in its early days targeted AàI editing was only shown with the concomitant DNA-directed overexpression of ADAR along with an targeting RNA or the ..read more

Yesterday, oligonucleotide therapeutics developer Wave Life Sciences provided a high-level preview on how it will deploy its RNA Editing technology.  Accordingly, modulating protein-protein interactions and, even more so, increasing gene expression will be the declared mechanisms of action of development candidates following its lead candidate WVE-006 for alpha-1-antitrypsin disease (AATD ..read more

As the collapse of Silicon Valley Bank (SVB) is making the rounds, let's take a step back and ponder what it means for the RNA Editing space. SVB has been a prominent banking partner for start-ups in tech and biotech, willing to do business where traditional banks did not feel comfortable with the unique risk profiles and needs of such businesses.  Short-term, the failure means that some jobs ..read more

Korro Bio yesterday announced that it would collaborate with Genevant to develop liposomally formulated oligonucleotides for the ADAR editing of alpha-1-antitrypsin in the liver. This is a big surprise for the field since based on the successes in the oligonucleotide therapeutics industry in general and data from competitors Wave Life Sciences and ProQR in particular, it would have seemed ..read more

One of the attractive aspects of oligo-mediated ADAR RNA Editing is that it can piggyback on decades of oligo delivery R&D.  New breakthroughs in oligonucleotide delivery are therefore instantly applicable to and greatly enhance the value of the platform. In order to make extrahepatic target engagement of oligonucleotide therapeutics as robust as in the liver, various cell-targeting ligand ..read more