Wave Life Sciences to Focus RNA Editing on Gene Upregulation

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).

WVE-006 was recently licensed to GSK and should be the first RNA Editing candidate to enter clinical development later this year.  A big milestone for the field.   WVE-006 corrects a common single nucleotide mutation in the alpha-1-antitrypsin gene, Z-AAT, that causes both liver and lung manifestations of AATD. Z-AAT is retained in liver hepatocytes to cause cellular stress instead of being secreted to do its job and protect the lung.  As such, WVE-006 can be considered both a mutation corrector and gene function booster.

 

Mutations often scattered across genes

More often than not, however, mutations causing rare genetic diseases are scattered across a gene and precision genetic medicines targeting small segments of a gene at a time may thus only address a subset of patients.  A prime example is Duchenne Muscular Dystrophy where even exon 51 skipping which is the approach with the largest addressable patients still only serves 11-13% of the overall DMD population.

                                DMD patient segmentation according to skipped exon (from Wave Life Sciences presentation)

A very interesting indication for ADAR RNA Editing is Rett Syndrome (affects 1 in 10000 girls by age 12 in the US).  Here as well are the mutations scattered across the MeCP2 gene.  Almost half of those would be addressable by RNA Editing (including eliminating stop codons), but each individual target would be quite small.

So instead of targeting the specific mutations, ADAR Editing may also be used to screen all adenines in the MeCP2 transcript to identify those that lead to an increase in protein abundance and thus function either by stabilizing the resulting mRNA or by increasing MeCP2 stability.  While this approach would not apply to Rett Syndrome caused by 2 null mutations on the X chromosomes, a say 3x increase in activity of the chromatin CpG-binding protein may be enough to alleviate disease in a large fraction of Rett Syndrome patients with MeCP2 versions having reduced activity.  Or consider mutant CFTR proteins in cystic fibrosis with reduced channel activity. Increase the abundance of those CFTR mutant proteins and it should increase the overall desired activity.

The screening approach would also facilitate finding potent RNA editing oligos due to the flexibility and increase in targeting space as opposed to having to optimize the editing oligo around a small defined target site.

 

mRNA technology

Wave Life Sciences likened the gene upregulation approach as a simpler version of mRNA therapeutic technology.  Simpler, because it does not involve the delivery of long mRNAs which necessitates the use of LNPs and similar larger nanoparticle formulations due to mRNA stability requirements.  By contrast, RNA editing can be mediated by oligos ~30 nucleotides in length, short enough to be amenable to conjugation and oligo chemistry strategies already applied in RNaseH and splice modulation ASO and RNAi.

Smaller also means better tissue penetration and delivery to more target tissues.

Moreover, meaningful expression from an mRNA only occurs in short bursts so that the frequency of repeat administration is dictated by protein half-life.  Meanwhile, the administration frequency for oligo-mediated editing, due to the longer persistence of highly stabilized oligos, can be expected to be in the weeks and months.

It should be noted though that RNA editing would essentially upregulate what is already present in the cell (with the exception of the one editing change), whereas mRNA therapeutics in sensu strictu can generate entirely new proteins.

RNA editing would also not be the first oligonucleotide approach to mRNA upregulation.  RNA activation, the targeting of promoter-proximal regions using RNAi-type double-strand RNAs, and the targeting of upstream 5’ UTR mRNA elements with steric blocking antisense molecules as developed by Ionis Pharmaceuticals are competing approaches.  These, however, have so far either lacked the robustness or the flexibility in terms of sequence choice that AàI editing should afford.  

 

Now more than ever in biotechnology, companies need to carefully tease out the unique, differentiating advantages of a platform technology when selecting an indication.  RNA Editing leaders ProQR and Wave Life Sciences are in the fortunate position that they can apply the new biotech paradigm starting with their first RNA Editing candidates.  Biotech is ripe for a reboot and RNA Editing should have every ambition to be part of it.

 

Disclosure: I own both ProQR and Wave Life Sciences shares, though ProQR considerably more. 

Silicon Valley Bank Failure is Warning Against More RNA Editing Start-Ups

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 are at risk as small companies for which SVB was the only banking partner may not be able to make this month’s payroll in time, and 10-20% of uninsured deposits above the $250k FDIC limit may be lost forever. 

SVB’s failure is a crack in the system resulting from rampant inflation and the dramatic rise of interest rates in response.  It’s quite possible that other cracks, also among the more traditional banking sector, emerge soon due to an imbalance of short-term cash demands of bank customers and banking treasuries overweighted in bonds with long maturities that can now only be sold at a loss.   

Too many biotechs!

That SVB, along with a smaller crypto-catering bank (Silvergate), is among the first victims is largely due to biotechnology’s voracious appetite for capital, but an inability to raise more of it in the current environment.  Having too many companies developing the same platforms and targeting the same diseases in parallel, especially in the gene therapy, genome editing, and immune oncology spaces, has only exacerbated the interest rate problem. 

SVB is thus symbolic for the (bio)tech excesses in recent years, culminating with the Covid19 crisis where every little idea was transformed into a start-up with $100M of funding from the get-go housed in glitzy labs and offices in the most expensive hubs, run by entitled executives more focused on ESG issues than bringing their technologies to fruition.   Contrast this to 15 years ago when little biotechs like LNP pioneer Tekmira (Protiva then) did better science, developed platforms more rapidly while fighting off larger rivals, yet spending just $3-4M a quarter.

Take CRISPR genome editing.  It seems like every new Cas enzyme, every new enzyme tethered to Cas9 doing something, anything with DNA or the epigenetics around it needs a new cash-burning start-up.  Instead of for example licensing prime editing to Beam Therapeutics, founded on more advanced base editing technology from the same academic laboratory, the movers and shakers in the VC scene sought to exploit David Liu’s star scientist status to found yet another immature biotech company many years away from a potential product and with even more inexperienced management.  To add insult to injury, this has been taken to the extreme of selling Liu’s* genius to suggest that he has solved nucleic acid delivery where thousands of humble scientists have worked over decades on similar concepts.  Enter Aera Therapeutics with- hold your breath- $193M in start-up funding.  

* correction: the scientific founder behind Aera Therapeutics is another CRISPR researcher from MIT, Feng Zhang, not David Liu.  The message, however, is the same.

Every paper a new biotech it seems. Sorry, and with all due respect to those involved: this type of behavior is unacceptable and comes across as greed and hubris.

 

Not too late for RNA Editing

One of the reasons I like ADAR RNA Editing also as an area of investment is that it is a differentiated technology platform allowing for unique therapeutic approaches and, equally important, where there has not been this hype leading to an overproliferation of companies and inefficient use of capital.

It is also not surprising that the two most advanced companies in the space, ProQR and Wave Life Sciences, are not pure-play startups.  By contrast, the refinement of editing oligonucleotides here happens within companies with a decade of experience in oligonucleotide drug development, and at least in the case of Leiden-based ProQR, at a fraction of the cost of its start-up rivals KorroBio and ADARx based in the Boston and San Diego hubs, respectively.

I am highlighting KorroBio and ADARx because they are the two most prominent start-ups around synthetic oligo-based ADAR RNA Editing that have significantly benefited from the Covid19 boom in biotech financing, but where I fail to understand what they are bringing to the table and thus the point of their existence.  For example, I wrote about my surprise at Korro Bio going with LNP delivery for liver-targeted AATD.  This most likely comes down to their inexperience in oligonucleotide chemistry.

So here is my plea to the ADAR RNA Editing industry: we do not need to repeat the mistakes made in other areas of biotechnology.  Competition, such as the rivalry between Alnylam and Sirna Therapeutics in RNAi, is a good thing as it focuses the mind, but 2 or 3 strong ADAR Editing-based pure-plays are really enough, plus some platform adoptions by larger oligonucleotide therapeutics companies like Ionis, Arrowhead, or Alnylam and disease-specific licensing activities of Big Pharma; and if there are important advances in academia relevant for the space, tech licensing the old style is appropriate.

Korro Bio Opts for LNP in Liver-Directed Lead Program

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 obvious to employ GalNAc-conjugated editing oligonucleotides for alpha-1 antitrypsin-related liver disease.

Korro Bio is a privately held pure-play ADAR editing company that has raised more than $200M since 2020 and is developing oligonucleotides, as opposed to DNA-directed small editing RNAs, for mediating AàI conversion.  Given this substantial funding and what appears to be the ready availability of GalNAc, it is a big mystery to me why Korro has chosen intravenously administered LNPs and in the process is giving up substantial ownership in this program through the collaboration.

Just last month, Korro Bio and scientific founder Joshua Rosenthal published a selection strategy for efficient editing oligonucleotides.  The paper (Quiroz et al, 2023) finished off with experiments illustrating the need for extensive oligonucleotide modification, reminiscent of what ProQR and Wave Life Sciences have practiced, for effective ADAR editing.

 

Learnings from RNAi

One explanation for why Korro may have favored an intravenously over a subcutanously administered technology may be potency.  In yesterday’s press release and a recent Nature Biotechnology RNA editing industry article, the company is boasting that it wants to return serum alpha-1-antitrypsin levels to within the normal range.

A lofty goal and perhaps most readily achieved without having to balance the demands of chemical modification for stabilization purposes and inherent ADAR activation potency. 

In the earlier days of RNAi, Alnylam’s LNP-formulated Patisiran actually won out over an internal GalNAc competitor that didn’t quite have the potency and was also associated with toxicity.  Patisiran has also won the commercial race against a subcutaneously administered antisense oligonucleotide by Ionis due to superior clinical data.

Clearly, depending on the stage of chemical modification know-how with regard to a specific oligonucleotide modality, LNPs may be preferable even for the targeting of genes in hepatocytes.

Maybe Korro Bio does believe it still has a potency edge over the competition, and combining its oligonucleotides with LNPs may also get them faster into the clinic.

 

The Vivek Factor  

There is no reason to believe that in AATD an LDL receptor-targeted delivery strategy may be beneficial over an ASGPR-targeted one because of changes in receptor expression levels.

I would, however, not rule out that Korro Bio succumbed to the magic of the bewilderingly fast-talking executives from the Roivant universe (Genevant is a Roivant subsidiary).  I still cannot get over the fact that Tekmira handed over half the company plus LNPs to (now US Presidential candidate) Vivek Ramaswamy for some toxic small molecules scribbled on the back of an envelope.

When you hear Vivek on the campaign trail these days and his sharp fast talk full with twisted arguments that make your head spin, then I understand why people that for whatever reason like this energetic person may throw out reason and just want to trust this guy.  But beware: while making billions for himself and his family, he has lost many more of shareholders’ money for projects like the Alzheimer’s drug that he dug out from a dumpster and IPO’d at a valuation of over a billion USD.  I digress…

 

Until we see non-human primate data from Korro Bio and Genevant, I will count this candidate out of the race in AATD.  Whether ProQR will fill the void and throw down the gauntlet to Wave Life Science will be seen by its pipeline reveal at the end of this month.