The outbreak of the COVID-19 pandemic we are currently witnessing has affected every single person since the shelter-in-place took effect back in March 2020. It had forced us to stay inside our homes unless you were an essential worker or needed to carry out essential errands. As of January 2021, millions of people have been infected and thousands have died due to unforeseen circumstances. But what really is COVID-19 and what is being done so far to bring this pandemic under control? While you may have been using coronavirus and COVID-19 interchangeably, you are partially correct. Coronavirus is the umbrella term for a big family of viruses that can cause upper-respiratory tract illnesses. On the other hand, COVID-19 is an illness caused by a fatal type of coronavirus called SARS-CoV-2.
Now, we are struggling to battle a pandemic from a fatal evolution of a coronavirus named SARS-CoV-2 that is causing the disease coined to be COVID-19. In December 2019, the first case was identified in Wuhan, China, and is spread mainly through person-to-person contact. Compared to SARS and MERS, COVID-19 is significantly more contagious and deadly. New York Times has reported more than 90.4 million cases and more than 1 million deaths worldwide. As the number of cases continues to grow, the urge to find treatments becomes more and more pressing as each day passes.
The following are Larta alumni companies that are working relentlessly to develop therapeutic technologies for COVID-19.
NIH CAP program alumnus Mirimus Inc. specializes in engineering sophisticated RNAi rat models through a genome editing technology called CRISPR/Cas9. This creates an advanced platform that allows Mirimus to perform “target validation and toxicity assessment of novel candidate targets in vivo” and helps to better predict patient outcomes (Prem Premsrirut, CEO of Mirimus). The advantages this technology offers support Mirimus’s pursuit of COVID-19 research. First, it allows them to manipulate genes in rat models so that their cell membranes can be embedded with ACE2, a receptor present on mammalian host cells. ACE2 is the main receptor the virus interacts with to gain entry into the host cell. Second, Mirimus can engineer these rat models to cater to its clients’ needs by turning other targeted genomes on and off by demand. Because of these characteristics, pharmaceutical companies are able to take advantage of these models to test the effectiveness of their novel drugs that are being produced to fight COVID-19. For example, researchers are able to evaluate various side effects their drugs may impose on patients and help assess other possible consequences that may have been overlooked previously. The convenience of having rats that can similarly model human cells with ACE2 receptors allows companies to modify their drugs and increase their chances of success by learning more about their strengths and weaknesses.
Another NIH CAP alumnus has shifted the focus of their developed technology to help further advance the battle against this pandemic. Montana Molecular’s company mission is to build robust and easy-to-use fluorescent assays that respond to drug activity to reduce the risk and cost of drug discovery. In light of this pandemic, they are able to utilize their already existing technology to form a pseudovirus that has the spike protein found on the surface of SARS-CoV-2 and a pseudo host cell that has the receptor (ACE2) the virus uses to penetrate the host cell. This assay helps researchers understand the interaction between these two proteins. However, this interaction is only one step in understanding the activity of this virus.
Another big focus area is the activity that occurs within the host cell following the interaction. Recognizing this gap, Montana Molecular recently launched a unique biosensor assay called 3CLglow that allows “researchers to look at a specific enzyme activity occurring inside any cell type of interest” (Anne Marie Quinn, CEO of Montana Molecular). The enzyme of interest here plays a fundamental role in the process of viral replication, which is an important precursor to infectivity. If the drug is unsuccessful in suppressing the enzyme, fluorescent light will glow from the host cell. This means the enzyme will continue to fulfill its part in replication. On the other hand, if the drug is successful, no fluorescent light will be seen. This will indicate that the enzyme has been suppressed and will no longer carry out its function. The mechanism of this assay could greatly benefit pharmaceutical companies by testing the efficacy of their novel antiviral drug(s).
Last but not least, alumnus Karyopharm Therapeutics is a clinical-stage pharmaceutical company whose primary focus is to discover, develop, and commercialize novel first-in-class drugs that are directed against nuclear transport for the treatment of cancer and other major diseases. In July 2019, the U.S. FDA approved Karyopharm’s oral medication called selinexor or XPOVIO®. It was initially marketed to treat adult patients with relapsed or refractory multiple myeloma. However, they are now broadening the use of this drug to help treat patients with COVID-19. Selinexor is a drug that is used to inhibit a protein called XPO1, which ultimately serves as a train between the cell’s nucleus and cytoplasm. One of the main regulating proteins in the nucleus is the tumor-suppressing protein that detects the presence of any DNA damage. Unfortunately, in cancer cells, these tumor-suppressing proteins are transported out of the nucleus with the help of XPO1. As a result, these suppressing proteins can no longer carry out their primary function to stop the cell from proliferating at an uncontrollable rate. This is where selinexor acts to inhibit the function carried out by XPO1 so that the tumor-suppressing proteins could induce cell destruction.
In COVID-19 patients, one of the main proteins vital for the virus’s propagation is ACE2. As discussed earlier, ACE2 is the main receptor used by the virus to penetrate the mammalian host cell. Karyopharm’s goal of using selinexor is to lock the mRNA transcription of the ACE2 receptor in the nucleus. With the XPO1 inhibited, the mRNA cannot leave the nucleus to finish the synthesis of the receptor in the cytoplasm and, therefore, cannot be embedded on the surface of the host cell that would allow the virus to bind to. Karyopharm has recently completed Phase II of their clinical trials and is currently waiting on the FDA’s approval before continuing onto Phase III.
The three companies showcased here are only a snippet of the endeavors that are being taken on towards establishing eradicating COVID-19. We thank all of our current cohort companies and alumni for continuing their work in the fight against COVID-19. We will continue to update our community with these stories as we receive them.
Program Management Intern, Larta Insitute