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, TNFa and IL1ß) 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.
Public Health Relevance Statement: PROJECT NARRATIVE Viral pandemics (e.g., Spanish flu, H1N1/influenza, and COVID-19) have taken a huge toll on human health and welfare. Organ injury and death from viral infections are increasingly recognized to result from an imbalance in the host immune response as well as tissue damage caused by the virus. The proposed studies will employ preclinical models to test a new therapeutic that that uses a novel mechanism to rebalance the host immune response as well as protect tissue from virus-induced damage. It has the potential to prevent deaths from COVID-19, regardless of evolving viral variants.
Project Terms: SARS-associated corona virus 2; SARS-associated coronavirus 2; SARS-coronavirus-2; SARS-related corona virus 2; SARS-related coronavirus 2; SARSCoV2; Severe Acute Respiratory Coronavirus 2; Severe Acute Respiratory Distress Syndrome CoV 2; Severe Acute Respiratory Distress Syndrome Corona Virus 2; Severe Acute Respiratory Distress Syndrome Coronavirus 2; Severe Acute Respiratory Syndrome CoV 2; Severe Acute Respiratory Syndrome-associated coronavirus 2; Severe Acute Respiratory Syndrome-related coronavirus 2; Severe acute respiratory syndrome associated corona virus 2; Severe acute respiratory syndrome coronavirus 2; Severe acute respiratory syndrome related corona virus 2; Wuhan coronavirus; coronavirus disease 2019 virus; coronavirus disease-19 virus; hCoV19; nCoV2; 2019-nCoV; injury to tissue; tissue injury; injury to organs; organ injury; COVID-19 therapy; COVID19 therapy; COVID19 treatment; SARS-CoV-2 therapy; SARS-CoV-2 treatment; coronavirus disease 2019 therapy; 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