tag:blogger.com,1999:blog-78570541496754246092024-03-19T08:47:44.221+00:00RNAi Therapeuticsrnaitherapeutics.blogspot.com follows the development in RNAi Therapeutics from bench to clinic. Comments on basic science and clinical issues as well as investment opportunities in this rapidly evolving field. From siRNAs to Dicer, from Alnylam to Silence Therapeutics- it's here.
Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.comBlogger660125tag:blogger.com,1999:blog-7857054149675424609.post-83325052510671730212023-08-24T16:02:00.003+00:002023-08-24T16:02:27.139+00:00The Nucleic Acid Therapeutics Race to Revolutionize Alpha-1-Antitrypsin 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 Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com0tag:blogger.com,1999:blog-7857054149675424609.post-28604391064299554722023-07-24T06:49:00.002+00:002023-07-24T06:49:52.007+00:00Lightning Fast Wave Life Sciences Demonstrates High ADAR Editing Rates Across TargetsThere 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 Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com0tag:blogger.com,1999:blog-7857054149675424609.post-78445021634854435702023-07-14T19:49:00.003+00:002023-07-14T19:49:37.996+00:00Korro Bio To Become Third Publicly Listed ADAR Editing CompanyToday, 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,
Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com0tag:blogger.com,1999:blog-7857054149675424609.post-64271510674644817192023-04-29T20:36:00.001+00:002023-04-29T20:36:05.665+00:00Roche Impresses with Effective RNA Editing of Polyglutamine Repeat mRNA 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 Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com3tag:blogger.com,1999:blog-7857054149675424609.post-49679896503913291392023-04-26T22:39:00.001+00:002023-04-26T22:39:06.520+00:00RNAi Also Conquers the Central Nervous SystemIn 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 Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com1tag:blogger.com,1999:blog-7857054149675424609.post-31072787601852131142023-04-25T15:04:00.002+00:002023-04-25T15:04:20.715+00:00Oligonucleotides Break Through to the LungIt is days like today that I live for. Days when new platform technology data
is revealed that will change the practice of medicine and benefit patients for
a number of diseases of high unmet need. In this case asthma, IPF, COPD etc. Almost a decade after GalNAc started to revolutionize
oligonucleotide therapeutics delivery to the liver (hepatocytes) and turned oligonucleotides into Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com3tag:blogger.com,1999:blog-7857054149675424609.post-71327113388070290442023-04-04T07:31:00.003+00:002023-04-04T12:23:36.207+00:00ProQR and Partner Eli Lilly Demonstrate Oligonucleotide-induced RNA Editing in the CNS: A Major De-risking Event for the IndustryWith 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 Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com0tag:blogger.com,1999:blog-7857054149675424609.post-47439607696973665092023-03-23T18:39:00.001+00:002023-03-23T18:39:10.115+00:00Wave 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 (Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com0tag:blogger.com,1999:blog-7857054149675424609.post-52036593453089047052023-03-12T11:52:00.004+00:002023-03-13T20:46:34.125+00:00Silicon 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 Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com1tag:blogger.com,1999:blog-7857054149675424609.post-63890577099606770992023-03-09T20:37:00.004+00:002023-03-09T20:37:44.409+00:00Korro Bio Opts for LNP in Liver-Directed Lead ProgramKorro 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
Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com0tag:blogger.com,1999:blog-7857054149675424609.post-28552349438256411982023-02-15T10:59:00.000+00:002023-02-15T10:59:01.745+00:00Gentle Endosomal Escape to Expand Reach of Oligonucleotide TherapeuticsOne 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 Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com0tag:blogger.com,1999:blog-7857054149675424609.post-67812965064884326992023-01-31T18:51:00.011+00:002023-02-05T17:27:53.631+00:00A Visit to ProQRYesterday, I had the pleasure and privilege to
visit ProQR in Leiden (Netherlands).
Thank you, Sarah and Andy from IR, for making it happen! The goal of my visit was to see whether the people
and the context in which it all happens are conducive to ProQR's delicate quest of growing, leading, and establishing the immensely valuable RNA
Editing platform as a new therapeutic modality.&Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com8tag:blogger.com,1999:blog-7857054149675424609.post-32531964635458185232023-01-11T09:38:00.002+00:002023-01-11T21:33:01.751+00:00Reconsidering RNA Editing for Alpha-1-Antitrypsin DiseaseAlpha-1-antitrypsin (AAT) is the lead program in the RNA
Editing pipeline with Wave Life Sciences recently licensing its candidate to GSK. It is safe to assume that a
number of other companies are working on similarly developing RNA Editing drugs in the AAT area as well.
Developments in the competitive environment using other platforms such as gene knockdown (RNAi, ASO) and genome Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com4tag:blogger.com,1999:blog-7857054149675424609.post-50950310407617373522022-12-27T15:17:00.001+00:002022-12-27T15:17:20.933+00:00Eli Lilly Comes Back for More ADAR EditingBarely two weeks after
GSK took an exclusive license to the ADAR Editing industry’s leading pipeline
asset (alpha-1-antitrypsin) and other ADAR targets from Wave Life Sciences, Eli Lilly and ADAR pure-play
ProQR announced a major expansion of their RNA Editing partnership from a year
ago.
Here, I will lay out
what the deal says about the position of RNA Editing within the pharmaceutical
industryDirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com3tag:blogger.com,1999:blog-7857054149675424609.post-66678872749167611292022-12-15T10:02:00.000+00:002022-12-15T10:02:08.377+00:00GSK Partners with Wave Life Sciences for Access to RNA EditingThis week, we have seen further confirmation of the
increasingly recognized value within the pharmaceutical industry of Oligonucleotide Therapeutics in general, and RNA Editing in particular.
In a landmark deal, GSK obtained an exclusive license
from Wave Life Sciences to the RNA Editing industry’s lead, albeit still
preclinical WVE-006 development candidate for the treatment of
Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com1tag:blogger.com,1999:blog-7857054149675424609.post-56010383052158043212022-11-25T16:57:00.002+00:002022-11-25T16:57:36.389+00:00Increasing RNA Editing Target Space Through Chemical Modification 5’ of Target A Not all target adenines
(A) are created equally. It is well
documented (Schneider et al. 2014; Picardi et al 2015) that sequence context plays
an important role in rendering A ripe for editing. So to realize the full potential of the platform, it is important to optimize the editing oligos taking sequence
context into account. Chemical optimization will play
a critical role here.Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com3tag:blogger.com,1999:blog-7857054149675424609.post-48130830519172445862022-11-22T08:25:00.006+00:002022-11-22T19:12:53.768+00:00RNA Editing to Generate Protective VariantsLast week, ProQR participated at its first investor conference after a half year hiatus following a failed binary clinical read-out of a antisense splice modulator and corporate re-organisation to solely focus on RNA Editing.To raise awareness of the company as a serious contender in this exciting field, the CEO detailed the new corporate strategy of growing the
company as a major future Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com3tag:blogger.com,1999:blog-7857054149675424609.post-26794821911196597432022-11-14T16:42:00.004+00:002022-11-15T07:43:23.348+00:00Ionis Widens Its Modality HorizonsOver the weekend, blue
chip antisense oligonucleotide company Ionis and genome editing competitor
Intellia presented data on targeting prekallikrein (PKK) for treating
hereditary hemeangioedema (Ionis donidalorsen here, Intellia NTLA-2002 here).
Using CRISPR Cas9
endonucleolytic disruption of the KLKB1 gene coding for PKK following LNP delivery, Intellia came out as
the apparent winner in Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com1tag:blogger.com,1999:blog-7857054149675424609.post-764098923089478872022-10-27T10:49:00.006+00:002022-10-27T10:49:53.558+00:00Big Pharma Investments in RNA EditingWhen it comes to new
platform technologies, investors generally like to see their belief validated by
large pharmaceutical companies. In
addition to confirming the soundness of the scientific approach, in times when access
to capital is constrained, such partnerships also provide an important financing source.
In RNA Editing, Venture
Capital certainly has taken the charge (and risk) by Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com2tag:blogger.com,1999:blog-7857054149675424609.post-86611154548419401532022-10-15T11:28:00.001+00:002022-10-15T11:28:04.114+00:00At the Core of Highly Active RNA Editing Oligos Increasing the inherent potency of ADAR guide RNAs (AgRNAs) through chemical and structural means is critical for the success of RNA Editing. For activity, the AgRNAs need to pair with the elements around the target Adenosine (A) and activate resident cellular ADAR enzymes.There are 3 ADAR enzymes that are relevant for therapeutic RNA Editing: 2 isoforms of ADAR1 (p110, and the longer Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com2tag:blogger.com,1999:blog-7857054149675424609.post-28125692513335308062022-10-09T19:31:00.004+00:002022-10-09T19:31:37.629+00:00Landmark Chemical Modification Study Shows RNA Editing Ready for the Clinic At this stage, providing investors and the pharmaceutical industry with
a clear line of sight that RNA Editing can be readily translated from concept into
therapeutic reality is key to unlocking the next step-up in valuation.
A landmark study in March earlier this year by scientists from Wave Life
Sciences (Monian et al, Nature Biotech) on chemically modifying ADAR guide RNA oligos (I will Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com0tag:blogger.com,1999:blog-7857054149675424609.post-31280710662800164742022-10-06T08:59:00.003+00:002022-10-06T18:36:10.169+00:00RNA Editing Emerging as a Broadly Applicable Oligonucleotide Therapeutics ModalityThis feels like RNAi all over again. 20 Years
after my life-altering journey in RNAi Therapeutics started, I can’t shake a similar sensation for the almost boundless
therapeutic opportunities around RNA Editing.
RNA Editing in our context refers to the directed change from Adenine
(A) to Inosine (I) in an RNA molecule with ‘I’ being read as a ‘G’ by the molecular
machineries inside a cell. Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com7tag:blogger.com,1999:blog-7857054149675424609.post-89604936027364614762022-02-08T14:11:00.015+00:002022-02-09T10:32:58.775+00:00Reuters Article on Novavax: a Rebuttal [disclosure: I own shares in Novavax]
The protein-based vaccine by Novavax is about to become the
gold standard covid vaccine: proven to be highly efficacious and better tolerated than existing options with 3-shot and ease of multiplexing making it ideally suited for fighting variants along with flu in the future.Unfortunately, Nuvaxovid (aka Covovax) has not been widely available as
Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com0tag:blogger.com,1999:blog-7857054149675424609.post-69746008561164446092020-07-26T08:58:00.000+00:002020-07-26T18:58:45.057+00:00Strong Presumption Moderna Covid Vaccine Infringes on Arbutus IP
News last Thursday that
the US Patent Trial and Appeal Board (PTAB) upheld a broad liposomal
nanoparticle (LNP)-related patent added an interesting wrinkle to the race to develop a vaccine against covid19. Given the way that LNP delivery of mRNA is practiced today (see also below), the patent owned by Arbutus Biopharma greatly impacts on the development of some of the most prominentDirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com0tag:blogger.com,1999:blog-7857054149675424609.post-21890457166320790652020-05-19T22:01:00.000+00:002020-05-20T05:55:48.973+00:00Moderna Covid19 Vaccine Getting Off to Questionable Start
After Friday comments by Trump that the US would be back in business with or without a vaccine, a number of other world leaders were suddenly warning of and
contemplating a world without an effective Covid19 vaccine. This made me wonder whether early clinical data from Moderna Inc’s
closely watched mRNA Covid19 vaccine were being shared between Western governments.
Indeed, Dirk Hausseckerhttp://www.blogger.com/profile/18320439857875629714noreply@blogger.com0