James Kamau Dorcas

HAYMARKET MEDIA GROUP LTD Rheum Advisor Interview with Dr. Akiko Iwasaki Event Location: July 18th, 2022 Ubiqus 61 Broadway – Suite 1400 – New York, NY 10006 Phone:-  Fax:- Rheum Advisor Interview with Dr. Akiko Iwasaki [START RECORDING] INTERVIEWER: Better? DR. AKIKO IWASAKI: Oh, yeah. Good. Perfect. INTERVIEWER: Okay. We're all set. Okay. You're ready? DR. AKIKO IWASAKI: Yes. INTERVIEWER: Okay. So first question, what does this discovery mean for the future of SLE in regards to pharmacogenetics and genetics? DR. AKIKO IWASAKI: Yeah, so maybe I can start by explaining the discovery which is that we've been studying these gene tic elements called endogenous retro viruses, which are remnants of retro viruses that have integrated into our ancestor, ancestral genomes over millions of years. Now they occupy about 8% of our genome and these things, most of these elements have been mutated or truncated to not code for any proteins. However, there's a handful of these endogenous retroviral sequences that are still able to code for proteins. And we focused on the envelope which is the viral protein that is used to enter whole cells. These envelope proteins from these endogenous retroviruses to see if we make antibodies to these envelope proteins. What we found was that people in general, even healthy people make antibodies to this endogenous retroviral envelope proteins, but in lupus patients, these antibodies were found to be toxic in that when they bind to white blood cells, they stimulate the release of inflammatory factors that are implicated in lupus disease pathogenesis. So what our research showed is that the patients with lupus generate antibody responses against these endogenous retroviral envelope proteins that can trigger inflammatory responses. And what does it mean for pharmacogenetics and genetics in the future is that we need to account for like auto reactive antibodies against these endogenous retroviral envelope as part of the equation of lupus pathogenesis. And if we can interfere with that process in some way that might provide us with a path towards therapy in lupus patients. INTERVIEWER: Great. Thank you. You just mentioned that these findings might have the potential to spur the development of new treatment options for SLE. So theoretically, could the expression of the endogenous stretcher virus or their ability to produce B cells be pharmacologically target ed somehow? DR. AKIKO IWASAKI: Yeah, that is our hope is to find inhibitors that can prevent the development of these types of auto an tibodies against the envelope, or we can think about targeting such antibodies by either inhibitors or antibodies against these antibodies. There are many ways one can imagine HAYMARKET MEDIA GROUP Rheum Advisor Interview with Dr. Akiko Iwasaki July 18 t h , 20202 1 tackling this toxic antibodies that are generated in these lupus patients. We could also target the downstream effe cts of the antibodies such as the neutrophil activation that may be one path in whic h our insights can help develop a new therapeutics. INTERVIEWER: Right. And also, as you just mentioned, the auto antibody complexes stimulate the neutrophils to release NES, which works in inflammation in SLE. And this almost acts as a positive feedback loop. So is there one part of the loop that acts as more of a main driver than the other which part of the loop theoretically could make more sense to target from a pharmacological standpoint and could different parts of this loop be targeted simultaneously. Those are with us even further reducing the damage from SLE. DR. AKIKO IWASAKI: Yeah. So this nets that are released from the neutrophils are pretty toxic because it contains a lot of factors that can stimulate other immune cells and even cause blood clot and other issues when these are released inside the blood vessels. So there's a lot of you know, highly inflammatory cascade that can be engaged by net release. And, and so targeting neutrophils and preventing net release as well as potentially degrading the nets once, once they're formed by enzymes, that can chew up components of these nets. These are some of the hypotheses that we can sort of test in in vitro or in vivo model animal models to see whether targeting the nets can have a positive im pact on the lupus disease. You know, but I think it doesn't explain the entire lupus disease because the lupus is a very heterogeneous disease. Some people might be suffering from antibodies to the end retrovirus and nets while others may be suffering fr om too much interfere responses that are engaging other pathways. So we first need to identify whom among the lupus patients might benefit the best from targeting these pathways and then test the pharmacologic agents that can, you know, target the, the key driver of these diseases. INTERVIEWER: Great. So from a patient characteristic standpoint more than 90% of people with lupus, her women and lupus is most often diagnosed during the child of hearing years of 15 to 45 years. Black Americans, Hispanics, Asian Americans, and native Americans are two to three times at greater risk than white Americans. So was the expression of human endogenous, retro viruses, is that impact organ damage and SLE consistent across these patient populations and their rate of experiencing SLE? DR. AKIKO IWASAKI: Yeah, that's an excellent question. So vast majority of our patients were also female. I t wasn't even possible to do a male female comparison because so like vast majority are females in our cohort. But with respect to other potential racial differences and demographic differences, we did look at some of these issues, but because our number was limited, we couldn't really see any significant differences between people of HAYMARKET MEDIA GROUP Rheum Advisor Interview with Dr. Akiko Iwasaki July 18 t h , 20202 2 different racial backgrounds. So that would require a future much larger study to look into because we just can't do a small study and identify these potential differences. INTERVIEWER: Right. So you used the ERV map that you developed in 2018 to perform the analyses describing the study. This ERV map also led to similar discoveries in the underlying mechanisms of breast cancer. So we're wondering, do you think the ERV map has the potential to uncover the mechanisms of other rheumatic diseases? DR. AKIKO IWASAKI: We really hope so. We want people to use this earth map. We created and it's publicly available, and essentially this really makes us have a tool to dissect the role of different endogenous retroviral genes that are inside of our human genome in variety of different setti ngs including rheumatic diseases, but also cancer or newer degenerative diseases and even potentially aging. So we are currently applying similar types of immune profile to look at long COVID patients and long COVID is also female dominant. And that also happens in childbearing ages and there are some reports demonstrating that lupus related auto antibodies are elevated in people who go on to develop low COVID at the acute phase of COVID. So we feel that there may be some link between lupus and long COVID and we are excited to figure out whether that link may involve antibodies to the endogenous retro viruses. INTERVIEWER: Great. Well, those are all of my questions. I really appreciate you taking the time to answer them. And again, thank you for being such a good sport about the technical difficulties that occurred during your first 10 or so minutes. DR. AKIKO IWASAKI: Yeah, no problem. through all the questions. Yeah. I'm glad we were able to get INTERVIEWER: Yeah, yeah, me too. Yeah. Do you have any anything else you would like to add on the topic or anything else you want to mention? DR. AKIKO IWASAKI: Not really. Actually. We are right now doing a parallel study on another transposable element called line one, which is not the same as endogen retroviruses, but it's another member of retrotransposons and line one activation appears to be involved in the cerebellar ataxia, which is a condition that can be exacerbated with a viral infection as well as it has genetic components. And so we're very excited to look for involvement of other retrotransposons elements in disease settings. INTERVIEWER: Great. Thank you. Yeah. So I have no further questions. If you c ould email me this recording afterward, I can send the transcription company and get that settled. There's about of seven to 10 day turnaround on those. HAYMARKET MEDIA GROUP Rheum Advisor Interview with Dr. Akiko Iwasaki July 18 t h , 20202 3 So after that is all transcribed and I finish editing everything that should be done, hopefully by the end of the month, if not the beginning of August. DR. AKIKO IWASAKI: Okay, great. Actually, because I made you the host, I think you have the recording after this. INTERVIEWER: All right. Thank you. You're right. Okay. Yeah. I'll stop recording now then. DR. AKIKO IWASAKI: And if you don't have it let me know, but I think, yeah, it goes to your end. INTERVIEWER: Okay. I'm going to stop recording now, then. [END RECORDING] HAYMARKET MEDIA GROUP Rheum Advisor Interview with Dr. Akiko Iwasaki July 18 t h , 20202 4