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Principal Investigator: JEFFREY S GLENN
Organization: STANFORD UNIVERSITY
Fiscal Year: 2022
Award: $8,915,196
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT: Our overall objective is to develop a novel class of outpatient therapeutics targeting highly-
conserved RNA structures in the genomes of SARS-CoV-2 and other respiratory viruses of pandemic potential.
Using influenza A virus (IAV) as a proof-of-concept, we previously showed that: 1) adding high-resolution RNA
secondary structure target information into the design of antisense oligonucleotide (ASO)-based therapeutics
can greatly enhance antiviral efficacy over simply targeting conserved primary sequence, as can incorporating
into the ASO design the ability to recruit RNase H to the target site; 2) a single intranasal dose of a highly stable,
locked nucleic acid (LNA) ASO designed against a universally conserved RNA structure provides 100% survival
when given 14 days before, or 3 days after a lethal IAV inoculum; and 3) no resistance to our LNA has been
selectable. Applying a similar approach, via a process we now term “programmable antivirals,” to SARS-CoV-2,
we 1) rapidly identified highly conserved RNA structures; 2) designed LNAs against these targets and showed
that cryo-electron microscopy (cryoEM) of a structure led to improved LNA design; 3) demonstrated that our lead
LNAs have compelling in vitro and in vivo efficacy against reference and clinical isolates, including virus
harboring mutations that reduce vaccine efficacy (e.g. delta variant). Complementarily, we have pioneered a
novel strategy, named “Inforna,” to design small molecules that selectively bind viral RNA structures and inhibit
noncoding RNAs involved in human genetic diseases and RNA viruses, including SARS-CoV-2, some with
activities in the nM and pM range. The small molecules can be modified to recruit an endogenous nuclease, akin
to the RNase H-induced degradation by LNA ASOs. We term this type of small molecule a “ribonuclease
targeting chimera (RIBOTAC).” We now hypothesize that: 1) our lead LNA molecules—including one targeting
a RNA structure common to SARS-CoV-1 and MERS-CoV—already represent ideal development candidates;
2) the LNAs’ antiviral potency can be further enhanced; 3) the resulting LNAs will have a high barrier to the
development of resistance and be broadly active against wild-type and vaccine-resistant strains; 4) Inforna can
help design small molecules and RIBOTACs against our identified target structures; 5) our therapeutics are
combinable with other anti-SARS-CoV-2 agents; and 6) analogous approaches can be rapidly applied against
RNA viruses of pandemic concern. We will test these hypotheses by: 1) selecting a lead (and back up) LNA anti-
SARS-CoV-2 therapeutic from “second generation” LNAs informed by optimizations around current leads and
cryoEM structures of their targets; 2) advancing the lead LNA therapeutic towards the clinic by expanding the
in vitro and in vivo virology data package and performing requisite CMC and IND-enabling activities; 3) identifying
and optimizing small molecules and RIBOTACs against the same SARS-CoV-2 RNA targets; and 4) identifying,
characterizing, and targeting conserved candidate RNA structure targets in other RNA viruses of pandemic
potential and developing programmable LNA and small molecule/RIBOTAC therapeutics against them.
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variant><Development><Dorsum><Dose><Drugs><Electron Cryomicroscopy><Endoribonuclease H><Functional RNA><GS-5734><Generations><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic defect><Genome><HCV infection><Hepatitis C><Hepatitis C virus infection><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Human><Human Genetics><IFN><In Vitro><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Interferons><Intracellular Communication and Signaling><Lead><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Medication><Methods><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modern Man><Molecular Interaction><Multimodal 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