Covid therapies must look beyond the lungs
The “respiratory” disease strikes many organ systems, including the GI tract. Lumen is testing the world’s first oral therapy directed at this neglected aspect of Covid-19.
By Brian Finrow and Jim Roberts
Today, Lumen announced significant new federal funding covering a Phase 2 clinical trial of our Covid-19 product, LMN-301. It is, we believe, the world’s first clinical program directed specifically at the GI manifestations of Covid-19. Like everything Lumen Bio does, LMN-301 is unique!
We’ve written about LMN-301’s rationale before, but given the lack of awareness of this subject, this piece is significantly longer than our usual Medium posts. We’ve also included more references for those interested in exploring the primary literature directly.
Background on Lumen’s Covid-19 program
Briefly, LMN-301 consists of two antibody-like fusion proteins, derived in part from the binding domains of camelid single-domain antibodies (also called SdAbs, VHHs, and nanobodies). At a conceptual level, this is very similar to the two-antibody cocktail developed by Regeneron (REGEN-COV), but Lumen’s is intended for oral and inhalation delivery rather than IV infusion.
Why oral delivery? The most notorious features of Covid-19 are respiratory, but the virus also infects the GI epithelium with profound consequences. A GI-targeted therapy to eliminate this viral reservoir could not only improve patient outcomes but also block a possible transmission route that has been neglected because of the lack of scalable drug development options to go after it.
The product rationale can be broken into three parts, which we explore below:
1. Treating the direct GI symptoms of Covid-19
2. Blocking certain secondary symptoms
3. Partially blocking transmission
Rationale #1: the GI manifestations of Covid-19 are common; sometimes they are severe
Like the original SARS virus, SARS-CoV-2 infection is mediated by the cell surface receptor ACE2 and a host cell surface protease called TMPRSS2 (1). Both ACE2 and TMPRSS2 are highly expressed in airway epithelial cells (2), and it is now well-established that both are also highly expressed in epithelial tissues throughout the GI tract, including the stomach, ileum, and colon (3). By one estimate, ACE2 is expressed on intestinal epithelial cells at levels nearly 100 times greater than on respiratory epithelial cells (4).
Therefore, it is not surprising that GI infection by SARS-CoV-2 is widespread, with a majority of Covid-19 cases in one leading study presenting with both GI and respiratory symptoms, and 25% of cases presenting with only GI symptoms (5). An early Wuhan study found even higher rates, reporting GI symptom rates of 85% in severely ill patients and 79% in stable patients (6).
The story fits well with the natural history of coronaviruses. Many coronaviruses that infect livestock present primarily as enteritis. An example is the outbreak of swine acute diarrhea syndrome coronavirus (SADS-CoV) that occurred near Wuhan in 2016 (7). In humans, similarly, 25% of MERS cases and up to 73% of original SARS cases presented with significant gastrointestinal distress (8,9).
These findings have been echoed by cellular and molecular biology researchers. Experiments involving human small intestinal organoids show the virus uses the same mechanism to infect GI epithelial cells of various lineages (10) and efficiently reproduces there (11). SARS-CoV-1 can also replicate in the GI tract, and live virus can be isolated from stool samples (12). SARS-CoV-2 clearly infects GI tissues of the best available animal model, shedding live virus in the stool (13). Abundant SARS-CoV-2 capsid proteins can be found within GI epithelial cells of Covid-19 patients (13), supporting the hypothesis that viral replication is occurring there.
The infection is not innocuous. In humans, SARS-CoV-2 infects the gastrointestinal epithelium resulting in serious sequelae (14). Bhayana et al. found that “[b]owel abnormalities and cholestasis [are] common on abdominal imaging of inpatients with Covid-19[, and] patients who went to laparotomy often had ischemia, possibly due to small vessel thrombosis” (15) (Figure 2).
An Italian group of researchers reported similarly severe problems in three consecutive Covid-19 patients with severe GI distress. Remarkably, all three were otherwise asymptomatic and repeatedly tested negative for SARS-CoV-2 in nasopharyngeal swabs (16). By contrast, tests on the affected GI tissues revealed heavy SARS-CoV-2 infection.
And this is just speaking of the GI symptoms appearing in the initial acute infection by the virus. Long-duration GI symptoms are also common among those suffering from “long Covid,” which we think of as a somewhat distinct set of issues (more on this below).
In short, gastrointestinal symptoms are a serious but understudied complication of Covid-19. Lumen Bio is pleased to do something, finally, about this oversight.
Rationale #2: depleting the GI viral reservoir might abate other Covid-19 induced complications, including ARDS, liver damage, and related sequelae
The pathology discussed above — especially gastrointestinal necrosis and the associated inflammatory responses including systemic chemokine and cytokine release — may be a proximate or contributing cause of acute respiratory distress syndrome (ARDS) (17). A meta-analysis of 186 publications demonstrated an odds ratio of 2.94 linking GI SARS-CoV-2 infection with ARDS (6).
The idea that injury or infection in the gut may induce sepsis, ARDS (previously referred to as pulmonary dysfunction or ‘traumatic wet lung’), and multiple organ failure dates back almost a century (18). Recent work also supports a causal mechanism underlying the well-documented relationship between infection or other injury to the GI tract and severe systemic inflammation, including ARDS (19). One theory stems from the observation that the lungs and gut are connected via the mesenteric lymphatic system and the thoracic duct, and so bacteria that translocate across the intestinal lumen and pro-inflammatory effectors released during gut injury may be migrating to the lungs and inducing ARDS (18,20). The weight of evidence supports the conclusion that addressing the GI manifestations of Covid-19 may be important to resolving these often-fatal complications.
Here, some remarkable facts of organ topology are relevant. The surface area of human lung tissue — if “ironed flat” — is commonly said to be roughly equivalent to a tennis court, far larger than the skin’s surface area. All that wrinkled up surface area is necessary for efficient exchange of oxygen and carbon dioxide with the bloodstream. The same is true of the GI tract, but for facilitating nutrient absorption. Its surface area, ironed flat, would cover approximately 350 square feet (21). The GI tract is 30 feet long and saturated with immune cells, which constantly surveille its interior (the GI lumen) for signs of trouble. So it is understandable that immunologists refer to the GI tract is the body’s largest immune organ (22). As noted above, ACE2 is expressed at rates up to 100 times higher in the GI tract, so the potential for immunological mischief is obvious when you put everything together.
The GI viral reservoir may also be contributing to the serious liver damage seen in many Covid-19 patients (17). It has been reported that over 70% of hospitalized Covid-19 patients have abnormal liver function tests and more than 20% suffer liver damage (23). The route of liver infection has not yet been characterized, but the high level of expression of ACE-2 in cholangiocytes suggest that direct transmission from the intestine viral reservoir is possible. Moreover, small-molecule antiviral drugs such as remdesivir are associated with liver toxicity, indicating that alternative, non-hepatotoxic therapeutics are urgently needed for GI-focused treatments.
Rationale #3: clearing the GI tract may reduce transmission
Infectious SARS-CoV-2 virions can be isolated from the feces of both patients (24) and animal models of Covid-19 (13). In many subjects, viral RNA is detected in fecal samples long after virus is no longer detected in nasopharyngeal swab samples (25). (See also Figure 1 above.) It is often found in stool and rectal swabs in individuals without any respiratory symptoms of disease (26).
This raises the prospect that SARS-CoV-2 may spread by fecal-aerosol transmission, which was documented for the original SARS virus in 2003 (27,28). Nailing down transmission modes is extraordinarily difficult, particularly in the midst of a pandemic, which explains why reasonably minded scientists continue to debate the question. In the case of the original SARS virus, proving spread by fecal-oral transmission required building a full-scale section of a high-rise apartment building (Figure 3).
Many subjects with ongoing GI infection test negative in nasopharyngeal swabs, yet silently carry and potentially transmit the virus for weeks (26). (See also Figure 1.) Modeling of outbreak dynamics in China indicate that, “due to their greater numbers, undocumented infections were the source for 79% of documented cases” (29) leading to speculation that GI-driven transmission may be partially responsible.
So, where do things stand today? For SARS-CoV-2, our view is that — put in the terms of the O.J. Simpson trials — the evidence is strong enough to win a civil case (“preponderance of the evidence”) but not yet strong enough for a criminal conviction (“beyond a reasonable doubt”). More evidence is needed.
Still, given all the evidence above, it seems improbable that zero cases stem from the GI infection. But until now, there has never been a research tool able to trace the origin of viral aerosols for a virus like SARS-CoV-2, which infects both GI and respiratory epithelial tissues. Tracing origin is a much easier task for researchers of norovirus and rhinovirus — both of which are highly contagious viral infections, but which infect just one sort of tissue or the other. (Influenza is another potentially interesting case — there is surprisingly strong evidence that, like SARS-CoV-2, influenza also infects the GI tract (30).)
The Lumen Bio platform may be the best new tool available to tease out these causal relationships, a question we’re eager to explore.
Other aspects of Covid-19 that may be relevant
A recent Nature paper characterized how the human antibody repertoire matures over time in response to SARS-CoV-2, long after primary symptoms have resolved (31). But given our focus, we found it jarring to see the researchers demonstrate that viral protein can still be found in human GI epithelial cells as long as 5.7 months after initial diagnosis of Covid-19. Indeed, other studies have shown that many “Covid long-haulers” report persistent and sometimes severe gastrointestinal symptoms. To our knowledge, there are no other development programs in the world directed at these aspects of Covid-19.
Separately from the obvious implications for Covid long-haulers, a recent piece in Science speculated that chronic infections may be breeding grounds for dangerous new variants (32). This is most likely among those with compromised immune systems and others who benefit the least from active vaccines: exactly the sorts of folks who would be most likely to benefit from Lumen’s product. So, the product might help not just those suffering from the disease, it could indirectly help the rest of us too.
Some of these are questions for future study, however. Demonstrating a statistically significant effect on transmission, ARDS, and long-hauler symptoms means enrolling far more patients than would be feasible in this initial study.
Initially, we are focusing on redressing the direct symptomology (Rationale #1), which requires far fewer patients — hundreds, not thousands. But we will be gathering the requisite data to inform future study design, and there’s always the potential to be pleasantly surprised. So: stay tuned. With our collaborators at the Defense Health Agency and the TOGETHER Trial Consortium in Brazil and Canada, we are eager to get this trial underway and start learning something about these important but neglected aspects of Covid-19.
Brian Finrow is cofounder and CEO of Lumen Bioscience; Jim Roberts is Lumen’s cofounder and Chief Scientific Officer.
1. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr;181(2):271–280.e8.
2. Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020 May;26(5):681–7.
3. Gu J, Han B, Wang J. COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology. 2020 Mar 3;158:1518–9.
4. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology. 2020 May;158(6):1831–1833.e3.
5. Han C, Duan C, Zhang S, Spiegel B, Shi H, Wang W, et al. Digestive Symptoms in COVID-19 Patients with Mild Disease Severity: Clinical Presentation, Stool Viral RNA Testing, and Outcomes. Am J Gastroenterol. 2020 Apr 15;115(6):916–23.
6. Gul F, Lo KB, Peterson J, McCullough PA, Goyal A, Rangaswami J. Meta-analysis of outcomes of patients with COVID-19 infection with versus without gastrointestinal symptoms. Bayl Univ Med Cent Proc. 2020 May 29;1–4.
7. Zhou P, Fan H, Lan T, Yang X-L, Shi W-F, Zhang W, et al. Fatal swine acute diarrhoea syndrome caused by an HKU2-related coronavirus of bat origin. Nature. 2018 Apr;556(7700):255–8.
8. Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, Al-Rabiah FA, Al-Hajjar S, Al-Barrak A, et al. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis. 2013 Sep;13(9):752–61.
9. World Health Organization. WHO issues consensus document on the epidemiology of SARS. Wkly Epidemiol Rec. 2003 Oct 24;78(43):373–80.
10. Zang R, Castro MFG, McCune BT, Zeng Q, Rothlauf PW, Sonnek NM, et al. TMPRSS2 and TMPRSS4 mediate SARS-CoV-2 infection of human small intestinal enterocytes [Internet]. Microbiology; 2020 Apr [cited 2020 Jun 6]. Available from: http://biorxiv.org/lookup/doi/10.1101/2020.04.21.054015
11. Lamers MM, Beumer J, van der Vaart J, Knoops K, Puschhof J, Breugem TI, et al. SARS-CoV-2 productively infects human gut enterocytes. Science. 2020 May 1;eabc1669.
12. Leung WK, To K, Chan PKS, Chan HLY, Wu AKL, Lee N, et al. Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection. Gastroenterology. 2003 Oct;125(4):1011–7.
13. Kim Y-I, Kim S-G, Kim S-M, Kim E-H, Park S-J, Yu K-M, et al. Infection and Rapid Transmission of SARS-CoV-2 in Ferrets. Cell Host Microbe. 2020 May;27(5):704–709.e2.
14. Lin L, Jiang X, Zhang Z, Huang S, Zhang Z, Fang Z, et al. Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut. 2020 Jun;69(6):997–1001.
15. Bhayana R, Som A, Li MD, Carey DE, Anderson MA, Blake MA, et al. Abdominal Imaging Findings in COVID-19: Preliminary Observations. Radiology. 2020 May 11;201908.
16. Zamboni P, Bortolotti D, Occhionorelli S, Traina L, Neri LM, Rizzo R, et al. Bowel ischemia as onset of COVID‐19 in otherwise asymptomatic patients with persistently negative swab. J Intern Med. 2021 Aug 26;joim.13385.
17. Agarwal A, Chen A, Ravindran N, To C, Thuluvath PJ. Gastrointestinal and Liver Manifestations of COVID-19. J Clin Exp Hepatol. 2020 May;10(3):263–5.
18. Deitch EA. Gut-origin sepsis: Evolution of a concept. The Surgeon. 2012 Dec;10(6):350–6.
19. de Jong PR, González-Navajas JM, Jansen NJG. The digestive tract as the origin of systemic inflammation. Crit Care. 2016 Dec;20(1):279.
20. Deitch EA. Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction: Gut lymph and MODS. Ann N Y Acad Sci. 2010 Oct;1207:E103–11.
21. Helander HF, Fändriks L. Surface area of the digestive tract — revisited. Scand J Gastroenterol. 2014 Jun;49(6):681–9.
22. Soumekh AE, Katz PO. Common Gastroenterology Disorders in the Elderly. Clin Geriatr Med. 2021 Feb;37(1):xiii–xiv.
23. Chai X, Hu L, Zhang Y, Han W, Lu Z, Ke A, et al. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection [Internet]. Genomics; 2020 Feb [cited 2020 Jun 11]. Available from: http://biorxiv.org/lookup/doi/10.1101/2020.02.03.931766
24. Xiao F, Sun J, Xu Y, Li F, Huang X, Li H, et al. Infectious SARS-CoV-2 in Feces of Patient with Severe COVID-19. Emerg Infect Dis [Internet]. 2020 Aug [cited 2020 Jun 6];26(8). Available from: http://wwwnc.cdc.gov/eid/article/26/8/20-0681_article.htm
25. Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020 May;5(5):434–5.
26. Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med. 2020 Apr;26(4):502–5.
27. Gormley M, Aspray TJ, Kelly DA, Rodriguez-Gil C. Pathogen cross-transmission via building sanitary plumbing systems in a full scale pilot test-rig. Bach H, editor. PLOS ONE. 2017 Feb 10;12(2):e0171556.
28. Li Y, Duan S, Yu ITS, Wong TW. Multi-zone modeling of probable SARS virus transmission by airflow between flats in Block E, Amoy Gardens. Indoor Air. 2005 Apr;15(2):96–111.
29. Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, et al. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2). Science. 2020 May 1;368(6490):489–93.
30. Minodier L, Charrel RN, Ceccaldi P-E, van der Werf S, Blanchon T, Hanslik T, et al. Prevalence of gastrointestinal symptoms in patients with influenza, clinical significance, and pathophysiology of human influenza viruses in faecal samples: what do we know? Virol J. 2015 Dec;12(1):215.
31. Gaebler C, Wang Z, Lorenzi JCC, Muecksch F, Finkin S, Tokuyama M, et al. Evolution of antibody immunity to SARS-CoV-2. Nature. 2021 Mar 25;591(7851):639–44.
32. Kupferschmidt K. Do chronic infections breed dangerous new variants? Science. 2021 Aug 20;373(6557):848–848.