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. 

Tekmira Setting New Standards in mRNA Therapeutics…and They Have Only Started

Tekmira today presented impressive data on pre-clinical messenger RNA (mRNA) delivery to the liver and solid cancers (PR here, slide deck here).   The data presented at the AsiaTides in Tokyo greatly exceeded those reported in the literature, including a 4 log increase in potency of liver gene expression compared to the seminal paper by Kariko et al.paper (2008). 

Importantly, the formulation process and chemistry were optimized for mRNA delivery thus generating electron-dense ~80nm particles and easily surpassing >90% encapsulation efficiencies that are thought to be required to pass regulatory CMC muster.

Tumors giving liver run for its money

What had caught my eye when Tekmira presented firstmRNA delivery data at the Tuebingen mRNA conference in October 2013 and which was further substantiated in the present presentation, in terms of absolute gene expression, their mRNA delivery seems to perform as well if not better in liver cancer and non-liver cancer models compared to in normal hepatocytes.  This could be due to a less RNA degradative environment in tumors versus the liver of which an important function is detoxification.  This is supported by the fact that the duration of mRNA expression in tumors greatly exceeded that in the liver (a gene with a short protein half-life was used).

This made me think of the recent oncology spin-out (Onkaido)by mRNA Therapeutics company Moderna, the darling of mRNA Therapeutics which has raised around half a billion dollars in partnership money (AstraZeneca, Alexion, DoD) and fund raisings over the last 18 months alone.  The spin-out and internal focus on genetically defined orphan diseases may mean that Moderna would like somebody else to fund Onkaido, for example as part of a joint venture.  Remember, for most Big Pharma companies, RNA Therapeutics are first and foremost interesting for oncology as it allows them to go after the targets that their scientists have been dreaming about for so long yet were not able to drug.

Given that most of the de-risking in oncology drug development occurs late in clinical development, it is debatable whether Tekmira, already with a lead candidate in oncology (TKM-PLK1) should focus their in-house mRNA development attention towards oncology initially and whether this might not be better done as part of a spin-out/joint venture (Onkaido and/or Big Pharma).

For the liver, mRNA expression was detected in essentially every hepatocyte.  This supports the use of SNALP-mRNAs not only for the use of the liver as a factory for protein production, but also for diseases with defects in single genes expressed in the liver, including those genes that act only in the cell that they were expressed in (cell autonomous).  Compared to oncology, such indications would also allow for earlier clinical de-risking and together with orphan status mean that they better match the profile of a (still) sub $500M market cap company.

More upside

Given that Tekmira has only been working on mRNA Therapeutics for a year plus (1-year stability data were presented) and since simple off-the-shelf mRNA chemistry was used, one can only dream which diseases could be addressed and where the company could go with this, including developing their own mRNA Therapeutics instead of viewing it as a simple monetization opportunity. 

Tekmira mRNA developments that I am looking out for include advances in mRNA delivery to the lung epithelium.  Tekmira has been, and according to the presentation is still actively working on inhaled LNPs, and it would be logical if they adapted that effort towards mRNA delivery.  Expressing CFTR in lung epithelia for the treatment of cystic fibrosis (CF) would be an obvious target here that could rally a lot of support from various stakeholders (important for companies like Tekmira).  Gene therapy involving the inhalation/instillation of DNA to the lung has failed, in large part due to the difficulty of getting the DNA from the cytoplasm across the nuclear membrane into the nucleus.  Just like in RNAi, mRNAs only need to get into the cytoplasm, a much simpler task.  Moreover, in CF you should not need to get the mRNA into every cell.

A final opportunity for Tekmira is the co-formulation of mRNAs and siRNAs into a single LNP.  Imagine an oncology drug targeting both cancer drivers such as PLK1 and overexpressing tumor suppressors.

Oyasuminasai.

Disclosure: long TKMR.