This is a time where the biotech industry has to mobilize resources to
mitigate the impact of pandemic SARS-CoV-2.
Nucleic acid-based therapeutics are prime candidates in this battle because of the speed with which drug candidates can be designed and their specificity. This blog provides an overview of
efforts in this area with an emphasis on my two favorite (and IMO most promising) nucleic acid
approaches: RNAi Therapeutics and mRNA vaccines.
RNAi Therapeutics
RNAi Therapeutics (and by extension the competing antisense, ASO approach),
knocking down genes for therapy, can be used in two ways to address the
current pandemic.
First, the RNAi triggers could target the virus itself in an existing
infection. The hope would be that by
doing so the damage, mainly lung inflammation leading to respiratory distress,
can be mitigated sufficiently for the patient’s immune system to gain time and
strength to successfully overcome the infection. The question then would be how early would be
early enough.
The second approach would be to target a host factor critical for viral
replication. The cellular entry receptor
ACE2 is the most promising candidate target gene here.
This strategy seems particularly promising for prophylactically
protecting those at high-risk of an infection, e.g. medical personnel, as protection
may last for a month or so based on the very long durations of efficacy seen in
human studies targeting genes in the liver and early studies in the lungs of
sheep.
Application in a prophylactic setting would probably have the added delivery advantage
in that the lung would be less congested and thus more accessible. Also, delivery may not have to reach so deep
into the lung as it would need to during later stages.
Delivery
Theory is one thing, but getting the RNAi triggers to where they are
needed in the body is and has always been the main challenge for RNAi
Therapeutics. Unlike targeting genes in
the liver which is now well-established, RNAi in the lung is a re-emerging area
of RNAi development.
Given that COVID19 is a respiratory illness where the virus intrudes the
body via the respiratory epithelium, a local, inhaled delivery approach should be
adequate and also happens to be the most promising route for RNAi Therapeutics in addressing pulmonary disease.
In the early days of RNAi Therapeutics development, the world was facing
the SARS outbreak. Seemingly attesting to the promise of speed and specificity against emerging
pathogens, Sirnaomics (based in both the US and China) soon published a
high-profile paper on the efficacy of RNAi in a monkey model of SARS coronavirus.
In hindsight and with the benefit of 15 more years
of RNAi Therapeutics development up-and-downs, however, these results were
probably based on innate immunostimulatory artefacts given the use of unmodified
Tuschl-type RNAi triggers and a nasal instillation route of administration making employing sugar water as a carrier.
Today, however, RNAi Therapeutics is much more advanced and an approach
that utilizes aerosolized highly modified and thus stabilized RNAi triggers
seems most appropriate.
Arrowhead Pharmaceuticals has emerged
as the front-runner in lung RNAi and is close to filing for clinical study approval for addressing cystic fibrosis. Their
approach combines the two most promising elements of today’s RNAi Therapeutics. In addition to RNAi trigger stabilization,
Arrowhead is adding targeting ligands to their agents, in this case small moieties
targeting integrin on lung epithelial cells.
While Arrowhead has not announced their entry into the COVID19 race,
Sirnaomics and Alnylam Pharmaceuticals (along with partnered Vir Biotechnology)
have. While it is unclear what
particular approach Sirnaomics is using 15 years after their SARS work, Alnylam
will be using highly modified RNAi triggers.
Whether targeting ligands will be utilized or not is unknown to me (update: the press release refers to 'conjugates of siRNA' so a targeting ligand is likely).
Of note, Alnylam had suffered an anti-viral innate immunostimulatory fiasco with their first commercial RNAi development program around the same time that Sirnamoics
was working on SARS. That program was for the respiratory syncytial virus (RSV) and Alnylam should be able to capitalize on the the lung RNAi development experience back then.
Other RNAi-related companies with experience in inhaled lung delivery
are miRNA Therapeutics company Miragen (miRNAs are structurally quite similar
to RNAi triggers), Genevant/Arbutus (descendants of Tekmira which became famous
for their Ebola efforts), and Arcturus Therapeutics.
mRNA vaccines
Arcturus Therapeutics and Genevant are now focused on developing
messenger RNA (mRNA) therapeutics and vaccines, including for lung disease cystic fibrosis.
The most known name in this area is Moderna Therapeutics which has a
high-profile, government-sponsored vaccine effort against SARS-CoV-2. Ultimately, it is vaccines that will allow the world to fully recover from the COVID19 scare while therapeutics should
be used in a much more focused manner.
The delivery challenge for vaccines is also lessened by the fact that it
is a gain-of-function approach and that the immune system itself is expert at
spotting foreign, in this case viral antigen expression. The challenge here is that this is has to be achieved
in the right immunological context so that a fruitful immune response is
formed.
The fact that Moderna were the first to ship mRNA for imminent trials shows
how easy it is for mRNA to go from viral sequence to product candidate and drug
material production. While I used to
poke fun at Moderna for building factories and installing robots without
having much science behind it to fill the production halls, for emerging biothreats like SARS-CoV-2 this has proven to be prescient.
CureVac, an mRNA competitor of Moderna, has also announced their entree
into COVID19. While they may lag behind Moderna
in terms of robotics and manufacturing capacity, they should be more expert in vaccine development (‘a little innate immune stimulation by the mRNA agent
itself may go a long way’).
The most intriguing and differentiated entrant in the mRNA vaccine area
to me, however, is Arcturus Therapeutics (disclosure: no stock position, but
considering taking one) to me. This
is because they are using a self-replicating RNA ('STARR') that they claim to require ~40-fold
less RNA to be intramuscularly injected. Formulation into an LNP 'LUNAR' particle may further lower the required dose. Given that vaccinating the world will in the end also be a manufacturing
challenge, being able to start with 40-times or thereabouts less material is a
serious practical advantage.
COVID19 shall pass and therapeutics and vaccines will play an important
role here. Even more important, however,
is that everybody does their part in minimizing and slowing the spread of the
virus ('flatten the curve', #SocialDistancing), particularly to protect those most at risk without having to resort to
draconian measures.
