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Developing Breakthrough RNA Therapeutics for SARS-CoV-2 

With the potential to be in patients by end of this summer, the most promising COVID-19 research being undertaken at UMMS draws upon one of our institutional core strengths:  RNA-based therapeutics.  A leader in RNA biology for over 40 years, UMMS is home to Nobel Laureate, Craig Mello, whose discovery of RNAi (along with Andrew Fire), and Phillip Zamore, whose seminal work on elucidating the RNAi mechanism helped launch a new therapeutic approach to silencing genes. Today, two of Dr. Mello and Zamore’s colleagues, Anastasia Khvorova and Jonathan Watts, are developing a cocktail of small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) that are specific for SARS-CoV-2.


Scientists in the Khvorova lab identify the chemical and biological properties that drive small RNA tissue distribution, retention, cellular uptake and biological availability. Their goal is to deliver RNA-based therapies to tissues through chemical engineering. By screening a wide range of chemically engineered and naturally occurring bioactive conjugates, they have already identified novel chemical modalities that support delivery of robust amounts of siRNAs to the heart, kidneys, muscle, placenta, vasculature and brain—tissues previously unable to be targeted by RNAi.

The Khvorova lab is developing a cocktail of siRNAs specific for the SARS-CoV-2 virus that can be delivered to endothelial and epithelial lung cells targeting specific SARS-CoV-2 mRNAs, to significantly reduce viral replication. 

Watch Dr. Khvorova's talk on RNA Therapeutics: Informational drugs as a pandemic response tool


The Watts lab is developing new approaches to several classes of oligonucleotides with the goal of harnessing these molecules to make an effective therapeutic for disease. Oligonucleotides are short DNA or RNA molecules that have a wide range of applications. Nucleic acid chemical biology gives the unique opportunities to interact with cellular processes, to diagnose, and to treat disease. By synthesizing oligonucleotides that can bind to the messenger RNA, it may be possible to effectively turn off genes that cause illness and disease.

Scientists in the Watts lab are developing viable mechanisms for delivering antisense RNA oligonucleotides (ASOs) to the lungs, which can significantly reduce the expression of the SARS-CoV-2 viral genes. Recently, the Watts lab developed a way to deliver ASOs intratracheally, in other words, directly to the lung.

Watch Dr. Watt's talk on Fighting an RNA Virus with an RNA Drug

siRNA against COVID-4.png

SARS-CoV-2, the novel coronavirus, binds to ACE2 receptors (blue) on the cell to gain entry into the cell where it hijacks the cell's own machinery to replicate, overloading the cell with viral particles. Drs. Khvorova and Watts are designing tools to stop the virus from replicating and overloading the cell. These tools are called short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). They act as the cell's own "google" search to find their specific mRNA target. Khvorova designed a cocktail of three siRNAs and Watts designed a cocktail of three ASOs to target and bind specific conserved regions of the viral messenger RNA (mRNA) in the lung.  Once the siRNAs or the ASOs bind to their mRNA target, they destroy the mRNA, blocking the coronavirus from replicating. This approach can function both therapeutically for those who are infected, as well as prophylactically for those who have not yet been exposed but are “at-risk populations,” including medical professionals, the elderly, and the medically compromised.

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