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The principal objective is to determine the impact of phenelzine on the activation phenotype of T cells and myeloid cells during SARS-CoV2 infection
Full description
Investigators want to test in vitro (in France Stage 1), and in vivo in a phase 1b/2 clinical trial (Stage 2 in Australia) a widely used antidepressant (the monoamine oxidase inhibitor (MAOi) Phenelzine (Nardil*), repurposed as an antiviral drug to treat SARS-CoV-2. Indeed this proposal leverages extensive existing data on the epigenetic mechanism of action of phenelzine and new data suggesting that it has an anti-viral action against the SARS-CoV-2 virus.
Epigenetic drugs are promising antiviral treatments capable of modifying epigenetic tags and re-programming host and viral genomes. Epigenetic modulation could be useful at least at two steps: the entry of the virus, and the regulation of the immune response. The SARS-Cov-2 depends on ACE2 and TMPRSS2 to gain cellular entry. The reduction of the expression of these proteins could therefore be protective.
Recent clinical studies have demonstrated that, in addition to their effects on neurotransmitter regulation, anti-depressants also possess anti-inflammatory characteristics via impacting pro inflammatory cytokines production which are involved in the 'cytokines storm' during severe disease. (2). These patients also have fewer circulating functional T cells and NK cells and greater numbers of dysfunctional, exhausted CD8+ T cells (3). These abnormalities are probably deleterious and reduce the efficacy of anti-viral responses.
The in-depth and patented epigenetic, cellular, and structural analyses of human cell lines harbouring the SARS-CoV-2 infective machinery and capable of propagating the virus have shown that:
LSD1 inhibition with Phenelzine in recent, successfully completed phase 1B clinical demonstrate that Phenelzine reverses the dysfunctional T cell phenotype and restores durable memory responses in vivo in advanced, metastatic breast cancer patients. Importantly, no adverse impact on healthy volunteer immune systems was recorded as part of the phase 1B clinical trial (5). Preclinical data shows that aged individuals have exhausted T cells compared to young individuals and MAOi re-waken these T cells resembling younger people.
Thus, investigators propose that in patients with severe COVID-19 infection, who are predominantly elderly; where dysfunctional T cells is also a feature, Phenelzine would have additional benefits on their immune function without adverse effects.
Therefore, this proposal exploits a clear mechanism of action of Phenelzine: epigenetic regulation and is the first study to explore epigenetic mechanisms in SARS-CoV-2 infection. Modulation of the epigenetism could directly counteract the virus via an antiviral effect, and indirectly via the restoration of a functional immune response.
Phenelzine has been used for nearly 60 years to treat major depressive disorder. Its side-effects, most of which are minor, are well characterized, including in the elderly or immune vulnerable.
Investigators approach is highly flexible, since LSD1 inhibition targets two immune mechanisms - a specific viral uptake pathway and the efficacy of T cell responses. Give the safety and easy applicability of Phenelzine, it lends itself to combinatorial therapeutic approaches as and when other anti-viral show efficacy. From the mechanistic perspective, investigators epigenetic approach complements and contextualises genetic studies on COVID-19.
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The different scales for severity are as follows:
For the severe infection's patients' group:
For the obese patients 'group:
Exclusion criteria
80 participants in 9 patient groups
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Central trial contact
Olivier LAMBOTTE, Prof; Katia BOURDIC
Data sourced from clinicaltrials.gov
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