International PCT No. PCT/EP2021/082221, 18 november 2021

Inventors: Bulavin DV, Triana-Martinex F

SUMMARY OF THE INVENTION

The inventors have surprisingly discovered that the majority of macrophages in an old animal carry the markers of senescence. They speculate that an ageing-induced senescence is an important contributor to macrophage hyper-reactivity in COVID-19 patients. Thus, lowering the level of senescence induction or removing a fraction of senescent macrophages could contribute to reducing COVID-19-associated hyperinflammation. This could in turn lower the morbidity and mortality seen in COVID-19 patients, that is associated with excessive inflammation.

The inventors also showed that specific compounds are able to attenuate age-induced senescence in macrophages. Moreover, the inventors have discovered that not only macrophages, but other immune cells such as T cells (including exhausted T cells and Treg cells), are concerned by senescence. As shown in the Examples, the global picture is that the nicotinamide N- methyltransferase (NNMT) pathway is at the center of senescent state of macrphages (p- Macs). Indeed, the role of NNMT in the regulation of senescence and immunosuppression in old macrophages is key :

Activation of NNMT is linked to senescent-like phenotype in p16Hi0h macrophages.

Thus, inhibition of this enzyme through methylated nicotinamide (mNAM) (inhibitor towards NNMT), CD38 inhibitors (CD38 is an upstream donor of NAM that is required for the NNMT-dependent senescent-like phenotype in p16Hi0h macrophages), and/or AOX inhibitors (which would result in accumulation of methylated NAM – an inhibitor of NNMT) could be viable options to reduce macrophage senescence and immunosuppression linked with it.

The inventors have also discovered that in the context of this pathway, many compounds may be used to reach this purpose.

Thus, the present invention relates to the use of at least one compound chosen from dual inhibitors of the mammalian target of rapamycin (mTOR) and phosphatidylinositol 3- kinase (PI3K), NNMT inhibitors, Janus kinase 2 inhibitors, CD38 inhibitors, inhibitors of the enzyme ataxia telangiectasia and Rad3 related, aldehyde oxydase (AOX) inhibitors, anesthetic agents, antagonists of the histamine H1 receptor, pleuromutilin and its derivatives, topical antiseptic cations and serotonin-norepinephrine reuptake inhibitors, for treating a disease associated with macrophage senescence.

Preferably, the present invention relates to the use of at least one compound chosen from BGT226 and its salts, WAY600, PP121 , Gedatolisib, Bimiralisib, Dactolisib, Voxtalisib, Ruxolitinib, NNMT inhibitors including mNAM, Pacritinib, Berzosertib, CD38 inhibitor 78c, apigenin, Tamoxifen, 4-Hydroxytamoxifen, Raloxifene, Bazedoxifene and its salts, Butacaine, Terfenadine, Valnemulin and its salts, Clomifene and its salts, Cetrimonium and its salts, and Duloxetine and its salts for treating a disease associated with macrophage senescence.