COVID-19 Genetics: Study Shows Need For Identifying Genetic Biomarkers In COVID-19 Patients To Assess Responses To Drugs And Therapeutics
: Genetics, genomics and personalized or precision medicine is going to play a very critical role in treating the COVID-19 disease and more researches and experts have to start adopting this approach.
The specific SARS-CoV-2 variant that is at play and the patient’s full genetic will determine the success of treatment protocols and therapeutics.
In a new TMN propelled study, researchers from Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Institut Pasteur of Shanghai, Fudan University, ShanghaiTech University and Hangzhou Institute for Advanced Study by leveraging nucleotide triphosphate analog-induced cell death, unveiled genes that affect the import, export, and metabolism of pervasively used antiviral and anti-inflammatory drugs in the treatment of COVID-19 disease.
Immunomodulatory agents such dexamethasone and colchicine, antiviral drugs remdesivir, favipiravir and ribavirin, as well as antimalarial drugs chloroquine phosphate and hydroxychloroquine are currently used in the combat against COVID-191-16. However, whether some of these drugs have clinical efficacy for COVID-19 is under debate. Moreover, these drugs are applied in COVID-19 patients with little knowledge of genetic biomarkers, which will hurt patient outcome.
In order to answer these questions, the study team designed a screen approach that could employ genome-wide sgRNA libraries to systematically uncover genes crucial for these drugs’ action.
Here the study findings show genes crucial for the import, export, metabolic activation and inactivation of remdesivir, as well as genes that regulate colchicine and dexamethasone’s immunosuppressive effects. The study findings provide preliminary information for developing urgently needed genetic biomarkers for these drugs. Such biomarkers will help better interpret COVID-19 clinical trial data and point to how to stratify COVID-19 patients for proper treatment with these drugs.
The study findings were published on a preprint server and are currently being peer-reviewed for publication into a journal.
The world-wide spread of COVID-19, caused by the SARS-CoV-2, has paralyzed health systems and economies worldwide. As the quest for effective drugs and vaccines continues, scientists and healthcare workers turned towards drug repurposing efforts for treating this infection.
Certain notable examples of drugs currently used in this combat against COVID-19 are immunomodulatory agents such as dexamethasone and colchicine, antiviral drugs remdesivir, ribavirin, and favipiravir, as well as antimalarial drugs chloroquine and hydroxychloroquine. (although some have already been deemed as ineffective and even lethal in some cases, man are still being used in protocols in various countries)
Alarmingly due to the urgency and lack of relevant knowledge, most of these drugs have been applied with little consideration of genetic biomarkers.
Importantly considering a rapid disease progression and the availability of myriad treatment options,
we need to discern genetic modulators for each COVID-19 drug so patients can be matched to the most effective drug choice.
The study team by Dr Wei Jiang from the Shanghai Institute of Biochemistry and Cell Biology and the University of Chinese Academy of Sciences did just that by pursuing the first genome-wide CRISPR screen on the aforementioned COVID-19 drugs and revealed important data on both resistance and sensitization mechanisms.
Due to the lack of executable screen endpoints and lack of toxicity present, which are two substantial hurdles for genome-wide screens when antiviral drugs are concerned, the researchers decided to use nucleotide triphosphate analog-induced cell death as a surrogate screen endpoint to overcome these obstacles.
Summary and comparison of drug-metabolizing enzymes and transporters identified in genome-wide CRISPR screens using our platform. Red boxes indicate enrichment of sgRNA against a gene in corresponding drug screen, whereas blue boxes indicate depletion.
Dr Jiang explained their methodological approach, "From a method standpoint, this screening strategy is the first that is capable of employing genome-wide libraries to identify genetic biomarkers for antiviral drugs."
Basically the study team designed a screening approach that could utilize genome-wide single guide RNA libraries to discover genes indispensable for the tested drugs' action systematically. This approach is broadly applicable to many existing and emerging viral illnesses.
The study results suggest that several gene groups that are involved in autophagy, but also lipid and cholesterol synthesis, may significantly modulate the action of chloroquine drugs. In turn, such a list of genes may be useful to appreciate and guide the clinical use of chloroquine drugs.
In addition it was shown that alkaloid drug colchicine might not sufficiently suppress the immune response for symptom alleviation in many patients with a specific constellation of genes, and the study further shed light on exact cytotoxic mechanisms of microtubule poisons (i.e., a significant group of anticancer drugs whose death mechanisms are still unclear).
Significantly, the top hit in the researcher's ribavirin screen was adenosine kinase ie an enzyme that catalyzes adenosine diphosphate (ADP) formation from adenosine. This turns out to be the key to the antiviral activity of ribavirin.
The study also demonstrated essential roles of SLC29A3 (encoding a nucleoside transporter protein) and HINT1 (coding for homodimeric purine phosphoramides) in the importation and activation of remdesivir, while drug-transporting gene ABCC1 and dephosphorylation enzyme gene NT5C2 were unveiled as pivotal in exporting and inactivating the same drug.
Dr Jiang told Thailand Medical news, "Transportation, activating and detoxifying mechanisms uncovered in this screen may point to clinical biomarkers of COVID-19 drugs. If such knowledge could be established in the future, it may help better understand the efficacy of individual drugs in the context of COVID-19.”
The study findings also suggest that infected individuals with specific genetic variation may respond differently to remdesivir and favipiravir, but not to ribavirin. Moreover, medically relevant single nucleotide polymorphisms for many of the genes identified in this screen have been reported in the human population.
The team concluded that all the screens delineated in this study will help advance the understanding of the exact action of COVID-19 drugs, potentially revealing useful genetic biomarkers for highly targeted disease management.
The study team is assisting Thailand Medical News (TMN) in also conducting a massive study of various herbs and phytochemicals identified to treat COVID-19 in finding out the reactions of these specific herbs and phytochemicals and also as a blend towards various human host genetic markers in the COVID-19 context.
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