Page 21 - Annual report 2021-22

Annual Report 2021-22 |

Abhay Sharma

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Abhay Sharma’s lab works on systems biology for drug discovery and epigenetic inheritance.

Drug repurposing in COVID-19: Effective treatments are urgently needed to reduce morbidity and
mortality associated with Coronavirus disease 2019 (COVID-19), a global public health emergency. The
pathogenesis of COVID-19 includes an anti-viral host immune response accompanied by mild clinical
symptoms that, in some patients, may lead to a phase of hyperinflammation and cytokine storm that
can cause acute respiratory disease with significant mortality risk. Reducing excessive cytokine release
and its sequel is therefore considered as a rational strategy to treat severe COVID-19 patients. In the
earlier months of the pandemic, much attention was centred on hydroxychloroquine/chloroquine
(H/CQ) as a potential cure due to its supposed anti-cytokine properties, an expectation that was later
not supported by randomized controlled trials (RCTs). On the other hand, the anti-inflammatory and
immunosuppressive drug dexamethasone (DEX) was found to be effective in interfering with disease
progression and reducing overall COVID-19 mortality. Some of the several anti-cytokine biologics and
small molecule inhibitors, which are at various stages of evaluation, are also expected to emerge as
successful candidates. A major challenge in COVID-19 treatment is to identify specific patients who
may benefit from a particular therapy, as also identification of the timing of administration for
achieving optimum results. Towards addressing these requirements, a compendious analysis of
existing transcriptomic data – that associated with various COVID-19 phases, various randomized trial
tested agents, other repurposing candidates and anti-cytokines, and multiple cytokines – was
undertaken in this period. The approach was validated first, and then an unbiased, algorithmic analysis
of different COVID-19 phases conducted.

For testing the validity of a compendious approach, common differentially expressed genes (DEGs) in
different tissues in severe COVID-19 were compared with DEGs related to drug/anti-cytokine and
cytokine treatments in various conditions. Overall, COVID-19 genes showed opposite and same
regulation with respect to drugs/anti-cytokines and cytokines, respectively. This expected distinction
between drugs/anti-cytokines and cytokines, given the potential of the former in COVID-19 therapy
and of the latter in COVID-19 pathophysiology. Notably, H/CQ mainly showed COVID-19-like
regulation, consistent with RCT findings. Also, DEX and tocilizumab (TOZ), with settled and recent
therapeutic evidence in COVID-19, both showed, as expected, gene regulation opposite of that
observed in the disease. For further validation, the analysis was repeated with rheumatoid arthritis
(RA) replacing COVID-19, and again, the results were on the expected lines, based on the association
of the two groups of agents with RA treatment and pathophysiology. After this method validation, the
analysis was centred on repeating the comparison with different COVID-stages separately, instead of
severe COVID-19 as whole or RA. These stages relate to intensive care unit (ICU), non-ICU, discharged,
and deceased, ventilated, non-ventilated, and oxygen supplemented patients. In brief, etanercept
(ETC), followed by tofacitinib (TOF) and adalimumab (ADM), caused transcriptomic responses
predictive of treatment potential in ventilated and non-ventilated ICU phases, and in non-ICU stage.
Besides, canakinumab (CAM) showed potential for benefits in the high oxygen supplemention phase.
Cumulatively, ranking of drugs/anti-cytokines observed in a combined analysis led to the
recommendation that etanercept, for which no COVID-19 RCT had been reported, be trialled in ICU