Impact of a Monoamine Oxidase Inhibitor on the Phenotype of Blood Mononucleated Cells in Patients With COVID-19

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:

- The epigenetic enzyme (histone demethylase) LSD1 directly regulates the
SARS-CoV-2-binding domain of ACE2 and the protease active sites of TMPRSS2 (patented),
which are critical for viral entry and propagation within the host.

- MAOi, which target LSD1 activity, inhibit the ACE2/TMPRSS2 machinery, which
investigators hypothesize will prevent viral entry into the host cell to reduce viral
load, disease burden, and the emergence of cytokine storms. In support of novel dual
targeting viral blockage strategy recent work have shown that targeting TMPRSS2 or ACE2
alone has anti-viral activity (4).

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.