New target and new therapy for severe Covid-19 and viral hyperinflammation damage: renalase and renalase agonists

点击翻译按钮获取中文摘要

Abstract The SARS-CoV-2 host response is associated with wide-ranging immuno-inflammatory derangements and tissue injury. We are developing an innovative therapeutic, BP-1002, to both blunt inflammatory cytokines and protect tissues. BP-1002 has the potential to prevent organ injury and deaths from COVID-19, regardless of viral variants. BP-1002, is a renalase (RNLS) agonist - a recently discovered secretory protein that promotes cell survival and downregulates the inflammatory response by signaling through the plasma-membrane calcium-ATPase, ATP2B4 (PMCA4b) receptor, and activating growth and survival pathways (protein kinase B, JAK/STAT, and MAP kinase). This activity is contained in a 20-40 amino acid RNLS site. Because RNLS is a large protein complex requiring manufacturing, we designed and developed BP-1002, a proprietary 36−aa RNLS-based (97.3 % amino acid identity) that contains the RNLS activity site. This RNLS agonist is stable and easily manufactured using chemical synthesis. Preliminary data show that low plasma RNLS correlates with disease severity hospitalized COVID-19 patients; or in acute renal injury, cardiac injury, and pancreatitis, which are COVID- 19 complications. Also, BP-1002 blunted inflammatory cytokine production (IL6, TNFα and IL1β) in human blood exposed ex vivo to the S- and M-proteins of SARS-CoV-2; improved survival by 60% in mouse models of simulated viral disease (poly(I:C) or SARS-CoV-2 infection). BP-1002 or recombinant RNLS reduced cell and tissue injury through modulation of inflammation, preservation of vascular integrity, and apoptosis prevention. Additionally, in a mouse inflammation model, single doses of BP-1002 had activity lasting 6 (intravenous) or 10 (subcutaneous) hours. Further, chronic-dosing pharmacology studies in mice show a profile consistent with a desirable therapeutic index. These studies confirm the strong potential for BP- 1002 as a new therapeutic for COVD-19. BP-1002 may also be useful alone or in combination with other COVID-19 therapies. A candidate for testing is IL-6 inhibitors, which have shown varied benefits for COVID-19 therapy. We plan further proof of concept evaluation of BP-1002, alone or with potentially synergistic IL-6 inhibition, to blunt inflammatory cytokines, prevent tissue damage and death in several mouse COVID-19 models. In addition, we will compare the pharmacokinetics after 30-min infusion, the route of administration that will be used in patients, with those after a dose-response studies after SC admin using a viral mouse model. Lastly, additional analytical studies will allow specifications to be set for future production.