Selected Podcast
ACE2-Fc as a COVID-19 Antiviral Therapy
Jing Jin, MD, PhD, assistant professor in the Division of Nephrology and Hypertension and his team work to identify pathological mechanisms of kidney and vascular diseases. His work with the therapy ACE2-Fc was recently included in an article published by Robert Kruse, MD, PhD in F1000 Research discussing a potential therapy for the novel coronavirus, COVID-19. In this episode, Jin explains how the therapy could potentially be used to guard against and treat COVID-19 and highlights the important role cross-collaboration plays in facilitating discovery.
Featured Speaker:
Jing Jin, MD, PhD
The lab is generally interested in the pathological mechanisms of kidney and vascular diseases. We take a proteomic approach to study molecules that serve structural or functional roles in kidney filtration. Particularly, we are trying to understand how the kidney podocytes maintain and regulate their slit diaphragm, as well as their interactions with the glomerular basement membrane. Transcription:
ACE2-Fc as a COVID-19 Antiviral Therapy
Melanie Cole: This is the Northwestern Medicine Podcast on COVID-19 dated March 30th, 2020. Welcome. This is Better Edge, A Northwestern medicine Podcast for Physicians. I'm Melanie Cole and joining me today is Dr. Jing Jin he is a Assistant Professor in the Division of Nephrology and Hypertension at Northwestern Medicine. His research focuses on identifying pathological mechanisms of kidney and vascular diseases. His work with the therapy ACE 2FC was recently included in an article published by Robert Cruz in F1000 Research, discussing a potential therapy for the COVID-19 virus. Thank you so much Dr. Jin for joining us today. You recently published a study in the Journal Kidney International examining the use of ACE 2FC to provide long lasting hypertension control and organ protection. Can you please give us a brief overview of your study?
Dr. Jin: The study was conducted in collaboration with my colleague and a friend, Dr. Dan [inaudible 01:10], in which we tried to address a limitation to use ACE 2 to treat renal disease. As we know like Ace, ACE 2 is the transmembrane protein anchored to the cell surface. The idea of engineering a so-called soluble ways which is membrane anchor cleaved off so that it can be administrated in a form of an injectable drug. Has interested research labs and the biotech companies alike, but it was soon realized that the blood environment is unfriendly to ACE 2 which gets quickly cleared from circulating and degraded. This was where the product started. Our solution was a fusion protein with ACE 2 linked to immune globulin IgG [inaudible 02:02]. Through a well known mechanism. The new ACE 2 FC fusion protein is now protected from scavenger cells as an IgG like entity, and is now compatible with the circulatory system. Through fusing 2 FC, ACE 2 extensive serum half-life at least a hundred fold to about nine days just like IgG. My training background was in protein biochemistry and with that we also devise the new assay for measuring ACE 2 activity as an enzyme. In our 2018 paper, we measured the pharmacologic efficacy of ACE 2 FC in great detail, as compared to that of the untapped version, that's Glaxo Smith Kline committed to their clinical trial for arterial pulmonary hypertension. To reemphasize our new ACE 2 FC improved the pharmacol efficacy substantially.
Host: That's absolutely fascinating and although your work is looking at different disease and organ targets, scientists believe that ACE 2 FC could be a promising therapy for COVID-19. Can you walk us through how it could be used as a potential treatment, Dr. Jin?
Dr. Jin: Well, ACE 4 through it's catalysts of hormonal peptides such as angiotensin 2, regulates reninangiotensin system in areas such as blood pressure control, heart functions and the fluid balance. Soon after the SARS outbreak in 2003, it was discovered that the virus uses ACE 2 as it's receptor to invade cells. This type of opportunistic gateway receptor that a virus seeks in order to, infect its human host, is very common. The important thing to notice, once we know what the human receptor of virus utilizes, we can create a targeted strategy to block the virus from binding to that receptor. Following SARS, A couple of other Coronaviruses including COVID-19 were also founded to use their spike protein or S 1 protein brief, to bind to ACE 2 for cell entry. So the game plan for us is obvious, we can use our long acting ACE 2 FC as the COVID-19 trap, to prevent the virus from binding to its human receptor, and the spreading from cell to cell. What I want to say is, although ACE 2 FC was originally constructed for different diseases, researchers including ourselves now consider ACE 2 strategy, a potential antiviral for COVID-19.
Host: Wow. So importantly there's a worldwide spotlight on developing a vaccine for COVID-19 which is incredibly important, but what the author is proposing is not a vaccine but an antiviral as you just said. Can you explain the difference and implications between the two? And speak specifically about the different targets in vaccine versus an antiviral and the rigorous testing that's needed for both?
Dr. Jin: I'll talk about the target in vaccine development first. Evidently, much of the focus has also been on the spike protein of COVID-19 because it is the major antigen that our body's immune system seeks off the virus. This knowledge is guiding the current development of our vaccines. Your absolutely right about a rigorous testing that is needed for both vaccines and antivirals in patients. We have not experienced an outbreak like this for at least the generation and the speed is of the essence here in finding ways to develop vaccines and antivirals as fast as possible to save lives. We can already see rapid advancement in both rounds because ultimately we may need combined solutions of vaccine and antivirus to put an end to the current outbreak.
Host: Well then along those lines, the author proposes several different options for potential therapies but sites ACE 2 FC as the most promising option due to its potential ability to both block the virus and treat lung injury. Tell us a little bit more about ACE 2 FCs ability to repair lung injury, which I find fascinating to those with acute respiratory distress syndrome.
Dr. Jin: The author of the opinion article was referring to the ACE 2 function that has been shown to ameliorate the severity of the ARDS likely through down regulation of a combination of it's basal active peptide substrates. Therefore, there is potentially an added benefit to ACE 2s antiviral effect with regards to COVID-19, ultimately the human body is a complex system and the right answer has to come from rigorous testing in patients.
Host: So then what makes ACE 2 FC more appealing than other potential targets? Tell us a little bit about the half-life and longevity of protection.
Dr. Jin: So many repurpose the clinical drugs or drug combinations, as well as preclinical drugs are being tested for COVID-19 patients. We hope the effectiveness of some treatments will soon be confirmed and that would definitely help the current situation. As I alluded to earlier, the ACE 2 based strategy, as seen in the examples of SARS and now 63 and now the COVID-19 coral viruses, may have a broader spectrum for antiviral activities as long as the Coronaviruses invade cells through the human ACE 2 receptor. That means if ACE 2 FC is to be effective to treat COVID-19 patients, it can also likely to be effective in treating future Coronavirus outbreaks. In other words, we can be more ready in fighting future Coronaviruses. And that is a potential advantage over other antiviral drugs.
Host: Well. Speaking of longevity, the author also proposes ACE 2 FC as a way to protect our healthcare workers on the front lines. So important right now. Can you tell us a little bit more about that?
Dr. Jin: So far we have discussed the treatment of patients. The longevity of ACE 2 FC, which lasts for one to two weeks, means that it can be used in theory, prophylactically to protect our healthcare workers, and also uninfected family members who are taking care of COVID-19 patients at home. This is the unique characteristic of the biologic. We have already tested ACE 2 FC to be well tolerated in animal studies at high dosages.
Host: So along those lines then, has any work begun to develop the therapy outlined in the article? Tell us a little bit more about that.
Dr. Jin: Well, a few that are evolving too rapidly for me to summarize here also, I am not aware of any drug development initiatives with ACE 2 FC in particular by pharmaceutical companies. New drug development takes time. Since COVID-19 outbreak I've suggested ACE 2 FC to our collaborator and the research sponsor company who is raising money to fund their COVID-19 project. On my side, my own lab is conducting new research on ACE 2 FC to further optimize the futures construction towards a manufacturing ready prototype, so we're interacting with colleagues and industry partners. I learned a lot in regards to finding the ways to translate basic research discoveries into clinical applications.
Host: You're doing such important work, Dr. Jin, as we wrap up, what else would you like physicians and scientists to know about your work as it relates to COVID-19?
Dr. Jin: Thank you. To me, I think the greatest excitement in doing research is that discoveries are often interconnected in a rather unexpected way. Our ACE 2 FC research started from hypertension but now intersects with COVID-19, which is a perfect example of that.
Host: In summary, Dr. Jin, tell other physicians what you would like them to know about the possibilities and your research as it relates to COVID-19.
Dr. Jin: Yeah, I think research collaboration is very important in our field, so constantly we learn new ideas from our colleagues. So this created a very unifying environment in fighting together of this deadly virus.
Host: Thank you so much, Dr. Jin, and keep up the great work. Thank you again for joining us. And that concludes this episode of Better Edge, A Northwestern Medicine Podcast for Physicians. To refer your patient, or for more information on COVID-19, please visit our website at nm.org to get connected with one of our providers. Please remember to subscribe, rate, and review this podcast and all the other Northwestern Medicine Podcasts. I'm Melanie Cole.
ACE2-Fc as a COVID-19 Antiviral Therapy
Melanie Cole: This is the Northwestern Medicine Podcast on COVID-19 dated March 30th, 2020. Welcome. This is Better Edge, A Northwestern medicine Podcast for Physicians. I'm Melanie Cole and joining me today is Dr. Jing Jin he is a Assistant Professor in the Division of Nephrology and Hypertension at Northwestern Medicine. His research focuses on identifying pathological mechanisms of kidney and vascular diseases. His work with the therapy ACE 2FC was recently included in an article published by Robert Cruz in F1000 Research, discussing a potential therapy for the COVID-19 virus. Thank you so much Dr. Jin for joining us today. You recently published a study in the Journal Kidney International examining the use of ACE 2FC to provide long lasting hypertension control and organ protection. Can you please give us a brief overview of your study?
Dr. Jin: The study was conducted in collaboration with my colleague and a friend, Dr. Dan [inaudible 01:10], in which we tried to address a limitation to use ACE 2 to treat renal disease. As we know like Ace, ACE 2 is the transmembrane protein anchored to the cell surface. The idea of engineering a so-called soluble ways which is membrane anchor cleaved off so that it can be administrated in a form of an injectable drug. Has interested research labs and the biotech companies alike, but it was soon realized that the blood environment is unfriendly to ACE 2 which gets quickly cleared from circulating and degraded. This was where the product started. Our solution was a fusion protein with ACE 2 linked to immune globulin IgG [inaudible 02:02]. Through a well known mechanism. The new ACE 2 FC fusion protein is now protected from scavenger cells as an IgG like entity, and is now compatible with the circulatory system. Through fusing 2 FC, ACE 2 extensive serum half-life at least a hundred fold to about nine days just like IgG. My training background was in protein biochemistry and with that we also devise the new assay for measuring ACE 2 activity as an enzyme. In our 2018 paper, we measured the pharmacologic efficacy of ACE 2 FC in great detail, as compared to that of the untapped version, that's Glaxo Smith Kline committed to their clinical trial for arterial pulmonary hypertension. To reemphasize our new ACE 2 FC improved the pharmacol efficacy substantially.
Host: That's absolutely fascinating and although your work is looking at different disease and organ targets, scientists believe that ACE 2 FC could be a promising therapy for COVID-19. Can you walk us through how it could be used as a potential treatment, Dr. Jin?
Dr. Jin: Well, ACE 4 through it's catalysts of hormonal peptides such as angiotensin 2, regulates reninangiotensin system in areas such as blood pressure control, heart functions and the fluid balance. Soon after the SARS outbreak in 2003, it was discovered that the virus uses ACE 2 as it's receptor to invade cells. This type of opportunistic gateway receptor that a virus seeks in order to, infect its human host, is very common. The important thing to notice, once we know what the human receptor of virus utilizes, we can create a targeted strategy to block the virus from binding to that receptor. Following SARS, A couple of other Coronaviruses including COVID-19 were also founded to use their spike protein or S 1 protein brief, to bind to ACE 2 for cell entry. So the game plan for us is obvious, we can use our long acting ACE 2 FC as the COVID-19 trap, to prevent the virus from binding to its human receptor, and the spreading from cell to cell. What I want to say is, although ACE 2 FC was originally constructed for different diseases, researchers including ourselves now consider ACE 2 strategy, a potential antiviral for COVID-19.
Host: Wow. So importantly there's a worldwide spotlight on developing a vaccine for COVID-19 which is incredibly important, but what the author is proposing is not a vaccine but an antiviral as you just said. Can you explain the difference and implications between the two? And speak specifically about the different targets in vaccine versus an antiviral and the rigorous testing that's needed for both?
Dr. Jin: I'll talk about the target in vaccine development first. Evidently, much of the focus has also been on the spike protein of COVID-19 because it is the major antigen that our body's immune system seeks off the virus. This knowledge is guiding the current development of our vaccines. Your absolutely right about a rigorous testing that is needed for both vaccines and antivirals in patients. We have not experienced an outbreak like this for at least the generation and the speed is of the essence here in finding ways to develop vaccines and antivirals as fast as possible to save lives. We can already see rapid advancement in both rounds because ultimately we may need combined solutions of vaccine and antivirus to put an end to the current outbreak.
Host: Well then along those lines, the author proposes several different options for potential therapies but sites ACE 2 FC as the most promising option due to its potential ability to both block the virus and treat lung injury. Tell us a little bit more about ACE 2 FCs ability to repair lung injury, which I find fascinating to those with acute respiratory distress syndrome.
Dr. Jin: The author of the opinion article was referring to the ACE 2 function that has been shown to ameliorate the severity of the ARDS likely through down regulation of a combination of it's basal active peptide substrates. Therefore, there is potentially an added benefit to ACE 2s antiviral effect with regards to COVID-19, ultimately the human body is a complex system and the right answer has to come from rigorous testing in patients.
Host: So then what makes ACE 2 FC more appealing than other potential targets? Tell us a little bit about the half-life and longevity of protection.
Dr. Jin: So many repurpose the clinical drugs or drug combinations, as well as preclinical drugs are being tested for COVID-19 patients. We hope the effectiveness of some treatments will soon be confirmed and that would definitely help the current situation. As I alluded to earlier, the ACE 2 based strategy, as seen in the examples of SARS and now 63 and now the COVID-19 coral viruses, may have a broader spectrum for antiviral activities as long as the Coronaviruses invade cells through the human ACE 2 receptor. That means if ACE 2 FC is to be effective to treat COVID-19 patients, it can also likely to be effective in treating future Coronavirus outbreaks. In other words, we can be more ready in fighting future Coronaviruses. And that is a potential advantage over other antiviral drugs.
Host: Well. Speaking of longevity, the author also proposes ACE 2 FC as a way to protect our healthcare workers on the front lines. So important right now. Can you tell us a little bit more about that?
Dr. Jin: So far we have discussed the treatment of patients. The longevity of ACE 2 FC, which lasts for one to two weeks, means that it can be used in theory, prophylactically to protect our healthcare workers, and also uninfected family members who are taking care of COVID-19 patients at home. This is the unique characteristic of the biologic. We have already tested ACE 2 FC to be well tolerated in animal studies at high dosages.
Host: So along those lines then, has any work begun to develop the therapy outlined in the article? Tell us a little bit more about that.
Dr. Jin: Well, a few that are evolving too rapidly for me to summarize here also, I am not aware of any drug development initiatives with ACE 2 FC in particular by pharmaceutical companies. New drug development takes time. Since COVID-19 outbreak I've suggested ACE 2 FC to our collaborator and the research sponsor company who is raising money to fund their COVID-19 project. On my side, my own lab is conducting new research on ACE 2 FC to further optimize the futures construction towards a manufacturing ready prototype, so we're interacting with colleagues and industry partners. I learned a lot in regards to finding the ways to translate basic research discoveries into clinical applications.
Host: You're doing such important work, Dr. Jin, as we wrap up, what else would you like physicians and scientists to know about your work as it relates to COVID-19?
Dr. Jin: Thank you. To me, I think the greatest excitement in doing research is that discoveries are often interconnected in a rather unexpected way. Our ACE 2 FC research started from hypertension but now intersects with COVID-19, which is a perfect example of that.
Host: In summary, Dr. Jin, tell other physicians what you would like them to know about the possibilities and your research as it relates to COVID-19.
Dr. Jin: Yeah, I think research collaboration is very important in our field, so constantly we learn new ideas from our colleagues. So this created a very unifying environment in fighting together of this deadly virus.
Host: Thank you so much, Dr. Jin, and keep up the great work. Thank you again for joining us. And that concludes this episode of Better Edge, A Northwestern Medicine Podcast for Physicians. To refer your patient, or for more information on COVID-19, please visit our website at nm.org to get connected with one of our providers. Please remember to subscribe, rate, and review this podcast and all the other Northwestern Medicine Podcasts. I'm Melanie Cole.