Ignite Creation Date:
2024-05-06 @ 2:37 PM
Last Modification Date:
2024-10-26 @ 1:34 PM
Study NCT ID:
NCT04375046
Status:
UNKNOWN
Last Update Posted:
2021-06-09
First Post:
2020-05-01
Brief Title:
Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP Could be Promising Treatment for COVID-19 Infection- and Its Inflammatory Complications Better Than Recombinant Human ACE2
Sponsor:
Kafrelsheikh University
Organization:
Kafrelsheikh University
Study Overview
Official Title:
Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP Could be Promising Treatment for COVID-19 Infection- and Its Inflammatory Complications Better Than Recombinant Human ACE2
Status:
UNKNOWN
Status Verified Date:
2021-06
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Bacterial ACE2
Brief Summary:
Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP could be promising treatment for COVID-19 infection- and Its inflammatory complications better than recombinant human ACE2
Mahmoud ELkazzaz1Tamer Haydara2Yousry Abo-amer3 Quan Liu4
1 Department of chemistry and biochemistry Faculty of Science Damietta University Egypt
2 Department of Internal Medicine Faculty of Medicine Kafrelsheikh University Egypt
3 HepatologyGastroenterology and Infectious Diseases Department Mahala Hepatology Teaching Hospital Egypt
4 School of Life Sciences and Engineering Foshan University Foshan Guangdong Province Laboratory of Emerging Infectious Disease Institute of Translational Medicine The First Hospital of Jilin University Changchun China
Abstract
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 has infected over 100 million people causing over 24 million deaths over the world and it is still expanding There is an urgent need for targeted and effective COVID-19 treatments which has put great pressure on researchers across the world for developing effective drugs This paper reviews the possibility of using Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP to treat SARS-CoV-2 based on the intracellular mechanism of SARS-CoV-2 transmission and consequences caused Angiotensin-converting enzyme 2 ACE2 plays a key role in cardiovascular physiology and pathology and its being currently being investigated as a potential covid-19 and acute lung failure treatment through several clinical trials The SARS-CoV2 binding site was identified as ACE2 a part of the RAAS which is known to protect the lung from injuries it has been postulated that SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity skewing the ACEACE2 balance to a state of heightened angiotensin II activity leading to inflammatory and oxidative organ damage as well as pulmonary vasoconstriction which can lead to acute lung injury Therefore treatment with recombinant soluble ACE2 protein and drugs that up regulate ACE2 may alleviate pulmonary complication In animal models including heart failure acute lung injury and diabetic nephropathy recombinant human ACE2 protein rhACE2 which is devoid of its membrane-anchored domain thus soluble has been shown to have beneficial effects Despite its positive effects rhACE2 is a glycosylated protein which necessitates a time- and cost-intensive protein expression system using mammalian or insect cells which may be inconvenient in drug production and medical economics Moreover we hypothesis that treating COVID-19 patients with recombinant soluble ACE2 protein may induce autoantibodies and T cells to cellular ACE2Furthermore rhACE2 may interact with spike protein based vaccine and worsen its effect These autoantibodies may generated by enforced presentation of the soluble Angiotensin-converting enzyme 2 ACE2 protein in a complex with COVID-19 Spike protein in fragment crystallizable FC Receptor positive Antigen Presenting Cells in the blood The development of autoantibodies might make injury and damage to the host epithelial cells and hamper their ACE2 dependent function in lungs intestine and testes which express ACE2 In addition to inducing platelet aggregation and thrombosis Although it has been stated that immune response associated with the chronic infusion of rhACE2 resulting in the degradation of rhACE226 this was not the case with B38-CAP no antibodies against B38-CAP were detected in the serum of mice infused with B38-CAP for two weeks In this case we suggest that bacterial engineering could be used to develop better protein drugs for COVID-19 treatment B38-CAP is an ACE2-like enzyme derived from bacteria that reduces hypertension and cardiac dysfunction Angiotensin-converting enzyme 2 ACE2 plays a key role in cardiovascular physiology and pathology and it is currently being studied in clinical trials to treat acute lung failure In mice B38-CAP treatment prevented angiotensin II-induced hypertension cardiac hypertrophy and fibrosis B38-CAP is an ACE2-like enzyme derived from bacteria demonstrating that evolution has shaped a bacterial carboxypeptidase B38-CAP to a human ACE2-like enzyme As a result we think that treating COVID-19-infected patients with Bacterial ACE2 like enzymes rather than human ACE2 may be preferable because it will perform the same role as human ACE2 and may not be recognized by COVID-19 spike protein
Keywords COVID 2019 Infection B38-CAP Bacterial ACE2 receptors -like enzyme rhACE226
Mahmoud ELkazzaz1Tamer Haydara2Yousry Abo-amer3 Quan Liu4
1 Department of chemistry and biochemistry Faculty of Science Damietta University Egypt
2 Department of Internal Medicine Faculty of Medicine Kafrelsheikh University Egypt
3 HepatologyGastroenterology and Infectious Diseases Department Mahala Hepatology Teaching Hospital Egypt
4 School of Life Sciences and Engineering Foshan University Foshan Guangdong Province Laboratory of Emerging Infectious Disease Institute of Translational Medicine The First Hospital of Jilin University Changchun China
Abstract
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 has infected over 100 million people causing over 24 million deaths over the world and it is still expanding There is an urgent need for targeted and effective COVID-19 treatments which has put great pressure on researchers across the world for developing effective drugs This paper reviews the possibility of using Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP to treat SARS-CoV-2 based on the intracellular mechanism of SARS-CoV-2 transmission and consequences caused Angiotensin-converting enzyme 2 ACE2 plays a key role in cardiovascular physiology and pathology and its being currently being investigated as a potential covid-19 and acute lung failure treatment through several clinical trials The SARS-CoV2 binding site was identified as ACE2 a part of the RAAS which is known to protect the lung from injuries it has been postulated that SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity skewing the ACEACE2 balance to a state of heightened angiotensin II activity leading to inflammatory and oxidative organ damage as well as pulmonary vasoconstriction which can lead to acute lung injury Therefore treatment with recombinant soluble ACE2 protein and drugs that up regulate ACE2 may alleviate pulmonary complication In animal models including heart failure acute lung injury and diabetic nephropathy recombinant human ACE2 protein rhACE2 which is devoid of its membrane-anchored domain thus soluble has been shown to have beneficial effects Despite its positive effects rhACE2 is a glycosylated protein which necessitates a time- and cost-intensive protein expression system using mammalian or insect cells which may be inconvenient in drug production and medical economics Moreover we hypothesis that treating COVID-19 patients with recombinant soluble ACE2 protein may induce autoantibodies and T cells to cellular ACE2Furthermore rhACE2 may interact with spike protein based vaccine and worsen its effect These autoantibodies may generated by enforced presentation of the soluble Angiotensin-converting enzyme 2 ACE2 protein in a complex with COVID-19 Spike protein in fragment crystallizable FC Receptor positive Antigen Presenting Cells in the blood The development of autoantibodies might make injury and damage to the host epithelial cells and hamper their ACE2 dependent function in lungs intestine and testes which express ACE2 In addition to inducing platelet aggregation and thrombosis Although it has been stated that immune response associated with the chronic infusion of rhACE2 resulting in the degradation of rhACE226 this was not the case with B38-CAP no antibodies against B38-CAP were detected in the serum of mice infused with B38-CAP for two weeks In this case we suggest that bacterial engineering could be used to develop better protein drugs for COVID-19 treatment B38-CAP is an ACE2-like enzyme derived from bacteria that reduces hypertension and cardiac dysfunction Angiotensin-converting enzyme 2 ACE2 plays a key role in cardiovascular physiology and pathology and it is currently being studied in clinical trials to treat acute lung failure In mice B38-CAP treatment prevented angiotensin II-induced hypertension cardiac hypertrophy and fibrosis B38-CAP is an ACE2-like enzyme derived from bacteria demonstrating that evolution has shaped a bacterial carboxypeptidase B38-CAP to a human ACE2-like enzyme As a result we think that treating COVID-19-infected patients with Bacterial ACE2 like enzymes rather than human ACE2 may be preferable because it will perform the same role as human ACE2 and may not be recognized by COVID-19 spike protein
Keywords COVID 2019 Infection B38-CAP Bacterial ACE2 receptors -like enzyme rhACE226
Detailed Description:
Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP could be promising treatment for COVID-19 infection- and Its inflammatory complications better than recombinant human ACE2
This is a small pilot study investigating whether there is any efficacy signal that warrants a larger Phase 2B trial or any harm that suggests that such a trial should not be done It is not expected to produce statistically significant results in the major endpoints The investigator will examine all of the biologic physiological and clinical data to determine whether a Phase 2B trial is warranted
Primary efficacy analysis will be carried only on patients receiving at least 4 doses of active drug Safety analysis will be carried out on all patients receiving at least one dose of active drug
It is planned to enroll more than or equal to 24 subjects with COVID-19 It is expected to have at least 12 evaluable patients in each group
Experimental group 04 mgkg rbACE2 IV BID and standard of care Control group standard of care Intervention duration up to 7 days of therapy No planned interim analysis
This is a small pilot study investigating whether there is any efficacy signal that warrants a larger Phase 2B trial or any harm that suggests that such a trial should not be done It is not expected to produce statistically significant results in the major endpoints The investigator will examine all of the biologic physiological and clinical data to determine whether a Phase 2B trial is warranted
Primary efficacy analysis will be carried only on patients receiving at least 4 doses of active drug Safety analysis will be carried out on all patients receiving at least one dose of active drug
It is planned to enroll more than or equal to 24 subjects with COVID-19 It is expected to have at least 12 evaluable patients in each group
Experimental group 04 mgkg rbACE2 IV BID and standard of care Control group standard of care Intervention duration up to 7 days of therapy No planned interim analysis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None