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Cited by 533Cancer Research and TreatmentsProbiotics and Fermented FoodsMicrobial Metabolic Engineering and Bioproduction

Developing a new class of engineered live bacterial therapeutics to treat human diseases

Open access
Charbonneau, Mark R., Isabella, Vincent M., Li, Ning, Kurtz, Caroline B.·2020·Nature Communications
DOI 10.1038/s41467-020-15508-1PMC PMC7142098
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Abstract

A complex interplay of metabolic and immunological mechanisms underlies many diseases that represent a substantial unmet medical need. There is an increasing appreciation of the role microbes play in human health and disease, and evidence is accumulating that a new class of live biotherapeutics comprised of engineered microbes could address specific mechanisms of disease. Using the tools of synthetic biology, nonpathogenic bacteria can be designed to sense and respond to environmental signals in order to consume harmful compounds and deliver therapeutic effectors. In this perspective, we describe considerations for the design and development of engineered live biotherapeutics to achieve regulatory and patient acceptance.

AI snapshot

Written from the paper’s full text.

TL;DR

This Perspective argues that engineered live biotherapeutic products (LBPs), especially nonpathogenic bacterial chassis such as *E. coli* Nissle 1917 and *Lactococcus lactis*, can sense and respond to disease environments and deliver therapeutic effectors. It reviews regulatory, design, testing, biomarker, manufacturing, and formulation considerations needed to translate engineered microbes into approved medicines.

Key findings

  • As of the paper, no recombinant LBP has been approved for medicinal use; recombinant LBPs in the United States are regulated by FDA/CBER, the FDA issued 2016 guidance on early clinical trials with LBPs, and the European Pharmacopoeia Supplement 9.7 set LBP quality standards effective April 2019.
  • Table 1 lists 13 engineered bacterial therapeutics in clinical development across chassis including *L. lactis*, *Listeria monocytogenes*, *Bifidobacterium longum*, *Staphylococcus epidermidis*, *E. coli* Nissle 1917, and *Salmonella* Typhi Ty21a; phases range from Phase 1 to Phase 2b, and SYNB1020 is listed as discontinued.
  • SYNB1618, an EcN strain engineered to degrade phenylalanine via phenylalanine ammonia lyase (PAL) and L-amino acid deaminase (LAAD), lowered blood Phe in a mouse PKU model and produced dose-dependent urinary hippuric acid in healthy non-human primates; a Phase 1/2a dose escalation in healthy volunteers and PKU patients (NCT03516487) showed it was generally well tolerated and produced dose-dependent hippuric acid.
  • Preclinical examples support engineered EcN and other strains for gut infections, metabolic disorders, and solid tumors, but design trade-offs include biocontainment, genetic stability, colonization versus non-colonizing dosing, and manufacturing/formulation constraints.

Methods

  • Design: Perspective/narrative review, not primary research; no systematic review or meta-analysis methods are stated.
  • Data or sample: literature synthesis plus Table 1 of engineered bacterial therapeutics in clinical development, with cited preclinical and clinical examples.
  • Main analysis: qualitative discussion of regulatory pathways, strain design, testing strategies, biomarkers, manufacturability, dosing, and formulations.

Limitations

  • Stated: lack of clear mechanistic understanding of disease pathophysiology and a paucity of disease- and effector-related biomarkers to establish dose-response relationships and target engagement; non-colonizing organisms require frequent dosing due to short residence time; few synthetic biology tools exist for strict anaerobes/commensals; regulatory guidance is general with minimal precedent.
  • Stated: manufacturing and clinical trade-offs, including possible viability losses from lyophilization/spray drying, constraints on biomass processes from environmental sensors, and genetic instability under selective pressure.
  • Evident: as a Perspective, it reports no original data, systematic search, or quantitative synthesis; Table 1 is a point-in-time list and may not be exhaustive; most cited therapeutic outcomes are preclinical or early-phase clinical.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41467-020-15508-1

Cites

93 of 93 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 100 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The human colon is an anaerobic environment.

    “Since the human colon is an anaerobic environment48, pathways and enzymes that do not require oxygen are preferred.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Molly, K., Vande Woestyne, M. & Verstraete, W. Development of a 5-step multi-chamber reactor as a simulation of the human intestinal microbial ecosystem. Appl. Microbiol. Biotechnol. 39, 254–258 (1993). source

      Not checked in the free run.

  • Premisecitation

    Hwang et al. demonstrated that the EcN-based gastrointestinal delivery of anti-biofilm enzyme, dispersin B (DspB), resulted in a reduction of pre-colonized P. aeruginosa abundance in both nematode and murine models.

    “For example, Hwang et. al. demonstrated that the EcN-based gastrointestinal delivery of anti-biofilm enzyme, dispersin B (DspB), resulted in a reduction of pre-colonized P. aeruginosa abundance in both nematode and murine models29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Hwang, I. Y. et al. Engineered probiotic Escherichia coli can eliminate and prevent Pseudomonas aeruginosa gut infection in animal models. Nat. Commun. 8, 15028 (2017). source

      Not checked in the free run.

  • Interpretationreasoning

    Engineered bacterial therapeutics possess a potential advantage over alternative microbiota-directed therapeutic approaches, such as fecal microbiota transplants or defined consortia of naturally occurring species, in that genetic engineering can confer functions that are not expressed by the endogenous microbiota.

    “Engineered bacterial therapeutics possess a potential advantage over alternative microbiota-directed therapeutic approaches, such as fecal microbiota transplants or defined consortia of naturally occurring species, in that genetic engineering can confer functions that are not expressed by the endogenous microbiota.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The human gut microbiota contributes to several metabolic and immune-mediated diseases, including obesity, malnutrition, intestinal inflammatory disease, and anti-cancer immunity.

    “Notably, members of the microbial community inhabiting the human gastrointestinal tract (termed the gut microbiota) contribute to several metabolic and immune-mediated diseases, including obesity2, malnutrition3, intestinal inflammatory disease4, as well as to anti-cancer immunity5,6.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006). source

      Not checked in the free run.

    • cites [3] Blanton, L. V., Barratt, M. J., Charbonneau, M. R., Ahmed, T. & Gordon, J. I. Childhood undernutrition, the gut microbiota, and microbiota-directed therapeutics. Science 352, 1533 (2016). source

      Not checked in the free run.

    • cites [4] Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008). source

      Not checked in the free run.

  • Premisecitation

    In both the United States and Europe, development of LBPs requires the demonstration of quality by establishing safety, reliability, robustness, and consistency of each batch produced.

    “In both the United States and Europe, development of LBPs requires the demonstration of quality by establishing safety, reliability, robustness, and consistency of each batch produced10,13.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] U.S. Department of Health and Human Services, Food and Drug Administration Guidance for Industry. Early clinical trials with live biotherapeutic products: Chemistry, manufacturing, and control information. www.fda.gov/downloads/Biologi%E2%80%A6/UCM292704.pdf (2016).

      Not checked in the free run.

    • cites [13] The European Pharmacopoeia Commission. Live biotherapeutic products for human use 9.7 (2019).

      Not checked in the free run.

  • Classified as probably not a substantial claim. 28
  • May combine two claims. 30

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Findingnone given

    Several recombinant bacterial therapeutics are currently being explored clinically, and patients are actively enrolling in these trials and accepting the associated risks.

    “Indeed, several recombinant bacterial therapeutics are currently being explored clinically (Table 1), and patients are actively enrolling in these trials and accepting the associated risks.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given

    Several engineered live bacterial therapeutics are currently entering early or mid-stage clinical development.

    “Several engineered live bacterial therapeutics are currently entering early or mid-stage clinical development and are poised to deliver the proof of concept needed to unlock the potential for this new class of therapeutics.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Escherichia coli Nissle 1917 (EcN) has been used as a probiotic since its isolation over 100 years ago.

    “Escherichia coli Nissle 1917 (EcN) has been used as a probiotic since its isolation over 100 years ago21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Beimfohr, C. A review of research conducted with probiotic E. coli marketed as symbioflor. Int. J. Bacteriol. 2016, 3535621 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Similar to EcN, Lactobacillus and Lactococcus genera do not colonize the human gut, thus allowing for predictive pharmacokinetic profiling of therapeutic strains.

    “Similar to EcN, these genera do not colonize the human gut, thus allowing for predictive pharmacokinetic profiling of therapeutic strains41,42.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Song, A. A., In, L. L. A., Lim, S. H. E. & Rahim, R. A. A review on Lactococcus lactis: from food to factory. Microb. Cell Factories 16, 55 (2017). source

      Not checked in the free run.

    • cites [42] Vesa, Pochart & Marteau. Pharmacokinetics of Lactobacillus plantarum NCIMB 8826, Lactobacillus fermentum KLD, and Lactococcus lactis MG 1363 in the human gastrointestinal tract. Aliment. Pharmacol. Ther. 14, 823–828 (2000). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Acto Bio Therapeutics currently has three engineered candidate strains in clinical development using the chassis organism Lactococcus lactis.

    “Acto Bio Therapeutics currently has three engineered candidate strains in clinical development using the chassis organism Lactococcus lactis (Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    LBPs must be studied in well-controlled clinical trials in the intended patient population to establish safety and efficacy.

    “They must also be studied in well-controlled clinical trials in the intended patient population to establish safety and efficacy10–12.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] U.S. Department of Health and Human Services, Food and Drug Administration Guidance for Industry. Early clinical trials with live biotherapeutic products: Chemistry, manufacturing, and control information. www.fda.gov/downloads/Biologi%E2%80%A6/UCM292704.pdf (2016).

      Not checked in the free run.

    • cites [11] Deal, C. Science and Regulation of Live Microbiome-Based Products Used to Prevent, Treat, or Cure Diseases in Humans - 09/17/2018 - 09/17/2018. (U.S. Food and Drug Administration, 2019). http://www.fda.gov/vaccines-blood-biologics/workshops-meetings-conferences-biologics/science-and-regulation-live-microbiome-based-products-used-prevent-treat-or-cure-diseases-humans.

      Not checked in the free run.

    • cites [12] Ross, J. J. et al. Considerations in the development of live biotherapeutic products for clinical use. Curr. Issues Mol. Biol. 10, 13–16 (2008).

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The genetic stability of an engineered live bacterial therapeutic is a concern for organisms that are intended to replicate within and/or colonize the patient's microbiota, and it may be possible for the strain to transfer engineered genetic material to other members of the endogenous microbiota.

    “However, the genetic stability of an engineered live bacterial therapeutic is a concern for organisms that are intended to replicate within and/or colonize the patient’s microbiota, and it may be possible for the strain to transfer engineered genetic material to other members of the endogenous microbiota.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The need for strict anaerobiosis may complicate manufacturing of these organisms.

    “However, the need for strict anaerobiosis may complicate manufacturing of these organisms.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    If there is a risk that the organism may reach other tissues, additional studies could be required to support the safety of the LBP.

    “However, if there is a risk that the organism may reach other tissues, additional studies could be required to support the safety of the LBP.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    EcN may interact with the intestinal epithelium to stimulate anti-inflammatory activities, as well as to restore and maintain intestinal barrier function.

    “Additionally, EcN may interact with the intestinal epithelium to stimulate anti-inflammatory activities24, as well as to restore and maintain intestinal barrier function25.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Fábrega, M. J. et al. Intestinal anti-inflammatory effects of outer membrane vesicles from Escherichia coli Nissle 1917 in DSS-experimental colitis in mice. Front. Microbiol. 8, 1274 (2017). source

      Not checked in the free run.

    • cites [25] Guo, S. et al. Escherichia coli Nissle 1917 protects intestinal barrier function by inhibiting NF-κB-mediated activation of the MLCK-P-MLC signaling pathway. Mediators Inflamm. 2019, 5796491 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Shepherd et al. engineered Bacteroides ovatus to metabolize porphyran; the resulting strain, B. ovatus NB001, was shown to stably engraft in the colonic microbiota of mice supplemented with porphyran in the diet, and the fecal abundance of this strain was titratable by modulating dietary porphyran.

    “Recently, Shepherd et al. engineered Bacteroides ovatus to metabolize porphyran, a marine polysaccharide that is rarely encountered in a Western diet44. The resulting strain, B. ovatus NB001, was shown to stably engraft in the colonic microbiota of mice supplemented with porphyran in the diet, and the fecal abundance of this strain was titratable by modulating dietary porphyran44.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Shepherd, E. S., DeLoache, W. C., Pruss, K. M., Whitaker, W. R. & Sonnenburg, J. L. An exclusive metabolic niche enables strain engraftment in the gut microbiota. Nature 557, 434–438 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many bacterial species have been evolutionarily selected for metabolic function within the mammalian gastrointestinal tract, and some probiotic organisms have a long history of safe use in humans.

    “Many bacterial species have been evolutionarily selected for metabolic function within the mammalian gastrointestinal tract, and some probiotic organisms have a long history of safe use in humans18,19.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Sonnenborn, U. Escherichia coli strain Nissle 1917-from bench to bedside and back: history of a special Escherichia coli strain with probiotic properties. FEMS Microbiol. Lett. 363, fnw212 (2016). source

      Not checked in the free run.

    • cites [19] Schultz, M. Clinical use of E. coli Nissle 1917 in inflammatory bowel disease. Inflamm. Bowel Dis. 14, 1012–1018 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    While genetic transfer is unlikely to be directly harmful to the patient, it may eliminate the competitive advantage of the engineered strain and undermine the efficacy of treatment.

    “While this genetic transfer is unlikely to be directly harmful to the patient, it may eliminate the competitive advantage of the engineered strain and undermine the efficacy of treatment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    LBPs are distinguished from probiotic supplements on the basis of their labeling claims, as most probiotics are regulated as dietary supplements and cannot make claims to treat or prevent disease.

    “LBPs are distinguished from probiotic supplements on the basis of their labeling claims, as most probiotics are regulated as dietary supplements and cannot make claims to treat or prevent disease10–12.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] U.S. Department of Health and Human Services, Food and Drug Administration Guidance for Industry. Early clinical trials with live biotherapeutic products: Chemistry, manufacturing, and control information. www.fda.gov/downloads/Biologi%E2%80%A6/UCM292704.pdf (2016).

      Not checked in the free run.

    • cites [11] Deal, C. Science and Regulation of Live Microbiome-Based Products Used to Prevent, Treat, or Cure Diseases in Humans - 09/17/2018 - 09/17/2018. (U.S. Food and Drug Administration, 2019). http://www.fda.gov/vaccines-blood-biologics/workshops-meetings-conferences-biologics/science-and-regulation-live-microbiome-based-products-used-prevent-treat-or-cure-diseases-humans.

      Not checked in the free run.

    • cites [12] Ross, J. J. et al. Considerations in the development of live biotherapeutic products for clinical use. Curr. Issues Mol. Biol. 10, 13–16 (2008).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Engineered LBPs can be designed to perform natural biological processes, such as the assimilation of ammonia into amino acids, at significantly increased rates and to produce effectors that are not native to bacteria, including human proteins.

    “Engineered LBPs can be designed to perform natural biological processes, such as the assimilation of ammonia into amino acids, at significantly increased rates14 and to produce effectors that are not native to bacteria, including human proteins16.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Kurtz, C. B. et al. An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans. Sci. Transl. Med. 11, eaau7975 (2019). source

      Not checked in the free run.

    • cites [16] Braat, H. et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin. Gastroenterol. Hepatol. 4, 754–759 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Gene cassettes conferring the ability to utilize porphyran could be horizontally transferred to other members of the gut microbiota.

    “Gene cassettes conferring the ability to utilize porphyran, for example, could be horizontally transferred to other members of the gut microbiota.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The colon harbors a diverse microbiota, but these organisms are predominantly localized to a loosely adherent layer of mucus.

    “Moreover, while the colon harbors a diverse microbiota, these organisms are predominantly localized to a loosely adherent layer of mucus49.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Welch, J. L. M., Hasegawa, Y., McNulty, N. P., Gordon, J. I. & Borisy, G. G. Spatial organization of a model 15-member human gut microbiota established in gnotobiotic mice. Proc. Natl Acad. Sci. USA 114, E9105–E9114 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies of radiolabeled E. coli in gnotobiotic mice have demonstrated that mucus-adherent E. coli display significantly higher rates of replication than those in the colonic lumen; no differences in replication rates were observed for Bacteroides thetaiotaomicron.

    “Studies of radiolabeled E. coli in gnotobiotic mice have demonstrated that mucus-adherent E. coli display significantly higher rates of replication than those in the colonic lumen50. Interestingly, no differences in replication rates were observed for Bacteroides thetaiotaomicron50.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Li, H. et al. The outer mucus layer hosts a distinct intestinal microbial niche. Nat. Commun. 6, 8292 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Strict anaerobes, including Bacteroides spp., may be useful chassis organisms due to their abundance in the colonic microbiota of humans, as well as their capacity to consume complex dietary and host-derived glycans.

    “Strict anaerobes, including Bacteroides spp., may be useful chassis organisms due to their abundance in the colonic microbiota of humans, as well as their capacity to consume complex dietary and host-derived glycans51.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Grondin, J. M., Tamura, K., Déjean, G., Abbott, D. W. & Brumer, H. Polysaccharide Utilization Loci: Fueling Microbial Communities. J. Bacteriol. https://doi.org/10.1128/JB.00860-16 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chen et al. demonstrated that an N-acylphosphatidylethanolamine (NAPE)-producing strain of EcN could significantly ameliorate symptoms associated with high-fat diet feeding in mice; mice treated with this recombinant EcN displayed reduced adiposity, insulin resistance, and hepatosteatosis compared to animals treated with an unengineered EcN control.

    “Chen et al. demonstrated that an N-acylphosphatidylethanolamine (NAPE)-producing strain of EcN could significantly ameliorate symptoms associated with high-fat diet feeding in mice. Mice treated with this recombinant EcN displayed reduced adiposity, insulin resistance, and hepatosteatosis compared to animals treated with an unengineered EcN control37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Chen, Z. et al. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J. Clin. Invest. 124, 3391–3406 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In 2016, the FDA issued a guidance document describing the regulatory considerations for conducting clinical trials with LBPs.

    “In 2016, the FDA issued a guidance document describing the regulatory considerations for conducting clinical trials with LBPs10.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] U.S. Department of Health and Human Services, Food and Drug Administration Guidance for Industry. Early clinical trials with live biotherapeutic products: Chemistry, manufacturing, and control information. www.fda.gov/downloads/Biologi%E2%80%A6/UCM292704.pdf (2016).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The European Pharmacopeia published a monograph setting the quality standards for LBPs for human use, in European Pharmacopoeia, Supplement 9.7; effective in April 2019.

    “The European Pharmacopeia published a monograph setting the quality standards for LBPs for human use, in European Pharmacopoeia, Supplement 9.7; effective in April 201913.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] The European Pharmacopoeia Commission. Live biotherapeutic products for human use 9.7 (2019).

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Chemically inducible promoters are less amenable to intratumoral applications, since achieving an effective concentration of the inducer molecule in situ may be challenging, and some such compounds are not Generally Regarded As Safe (GRAS) for human use.

    “However, chemically inducible promoters are less amenable to intratumoral applications, since achieving an effective concentration of the inducer molecule in situ may be challenging, and some such compounds are not Generally Regarded As Safe (GRAS) for human use.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Automated parallel bioreactor systems have accelerated fermentation process development by combining smaller volumes and higher throughput to enable greater iteration than traditional benchtop bioreactors.

    “In recent years, automated parallel bioreactor systems have accelerated fermentation process development by combining smaller volumes and higher throughput to enable greater iteration than traditional benchtop bioreactors84–86.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [84] Xu, P. et al. Characterization of TAP Ambr 250 disposable bioreactors, as a reliable scale-down model for biologics process development. Biotechnol. Prog. 33, 478–489 (2017). source

      Not checked in the free run.

    • cites [85] Sandner, V., Pybus, L. P., McCreath, G. & Glassey, J. Scale-down model development in ambr systems: an industrial perspective. Biotechnol. J. 14, e1700766 (2019). source

      Not checked in the free run.

    • cites [86] Manahan, M. et al. Scale-down model qualification of ambr® 250 high-throughput mini-bioreactor system for two commercial-scale mAb processes. Biotechnol. Prog. https://doi.org/10.1002/btpr.2870 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The selection of an appropriate animal model depends on the question being addressed, as the translational value of animal models varies by species and genotype.

    “The selection of an appropriate animal model depends on the question being addressed, as the translational value of animal models varies by species and genotype.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Human gastrointestinal anatomy and physiology is more closely approximated by pigs and non-human primates than by rodent models, but models of disease states may be unavailable in these large animal species.

    “Human gastrointestinal anatomy and physiology is more closely approximated by pigs and non-human primates than by rodent models80, but models of disease states may be unavailable in these large animal species.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Hatton, G. B., Yadav, V., Basit, A. W. & Merchant, H. A. Animal farm: considerations in animal gastrointestinal physiology and relevance to drug delivery in humans. J. Pharm. Sci. 104, 2747–2776 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    In vitro simulations can elucidate the kinetics of engineered circuit regulation and function over timescales that are relevant to human biology.

    “Moreover, these in vitro simulations can elucidate the kinetics of engineered circuit regulation and function over timescales that are relevant to human biology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Wei et al. engineered Bifidobacterium longum to express the proapoptotic compound, tumstatin; this strain was shown to inhibit tumor growth in a mouse model by various routes of administration.

    “In a similar study, Wei et al. engineered Bifidobacterium longum to express the proapoptotic compound, tumstatin68. This strain was shown to inhibit tumor growth in a mouse model by various routes of administration68.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Wei, C. et al. Bifidobacteria expressing tumstatin protein for antitumor therapy in tumor-bearing mice. Technol. Cancer Res. Treat. 15, 498–508 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    While several examples of effectors have shown promise preclinically, rigorous clinical trials will be required to determine whether these results translate to heterogeneous human cancers that have been recalcitrant to current modes of therapy.

    “While several examples of effectors have shown promise preclinically, rigorous clinical trials will be required to determine whether these results translate to heterogeneous human cancers that have been recalcitrant to current modes of therapy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Nutritional auxotrophies or kill switches can be utilized in engineered strains to prevent replication inside the host organism as well as to control the duration of therapeutic activity and limit the potential toxicity of an engineered strain to patients.

    “To help address these concerns, nutritional auxotrophies or kill switches can be utilized in engineered strains to prevent replication inside the host organism as well as to control the duration of therapeutic activity and limit the potential toxicity of an engineered strain to patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    The requirements for clinical development of engineered biotherapeutics, including diligent toxicology studies and adherence to regulatory guidelines, do not scale similarly and represent significant cost and effort for each candidate strain.

    “However, the requirements for clinical development of engineered biotherapeutics, including diligent toxicology studies and adherence to regulatory guidelines, do not scale similarly and represent significant cost and effort for each candidate strain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Oral administration of SYNB1618 was shown to significantly lower blood Phe concentrations in a mouse model of PKU, as well as to result in dose-dependent production of the PAL-specific urinary biomarker, hippuric acid, in healthy non-human primates.

    “Oral administration of SYNB1618 was shown to significantly lower blood Phe concentrations in a mouse model of PKU, as well as to result in dose-dependent production of the PAL-specific urinary biomarker, hippuric acid, in healthy non-human primates.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Isabella, V. M. et al. Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Nat. Biotechnol. 36, 857–864 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    E. coli has been shown to colonize the region surrounding the necrotic core of tumors after intravenous injection, and several reports have demonstrated the use of engineered E. coli strains to treat solid tumors in preclinical models.

    “For example, E. coli has been shown to colonize the region surrounding the necrotic core of tumors after intravenous injection9, and several reports have demonstrated the use of engineered E. coli strains to treat solid tumors in preclinical models15,62–65.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [9] Stritzker, J. et al. Tumor-specific colonization, tissue distribution, and gene induction by probiotic Escherichia coli Nissle 1917 in live mice. Int. J. Med. Microbiol. IJMM 297, 151–162 (2007). source

      Not checked in the free run.

    • cites [15] Chowdhury, S. et al. Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nat. Med. 25, 1057–1063 (2019). source

      Not checked in the free run.

    • cites [62] Yamada, T. et al. Apoptosis or growth arrest: modulation of tumor suppressor p53’s specificity by bacterial redox protein azurin. Proc. Natl Acad. Sci. USA 101, 4770–4775 (2004). source

      Not checked in the free run.

    • cites [63] Zhang, Y. et al. Escherichia coli Nissle 1917 targets and restrains mouse B16 Melanoma and 4T1 breast tumors through expression of Azurin protein. Appl. Environ. Microbiol. 78, 7603–7610 (2012). source

      Not checked in the free run.

    • cites [64] Li, R. et al. Expressing cytotoxic compounds in Escherichia coli Nissle 1917 for tumor-targeting therapy. Res. Microbiol. 170, 74–79 (2019). source

      Not checked in the free run.

    • cites [65] Ho, C. L. et al. Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention. Nat. Biomed. Eng. 2, 27–37 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    The selection of engineered therapeutic effectors is likely to be critical for efficacy in patients.

    “However, the selection of engineered therapeutic effectors is likely to be critical for efficacy in patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    While mice are readily available for preclinical studies, the oral bioavailability of small molecule drugs in humans and rodents have demonstrated poor correlation.

    “For example, while mice are readily available for preclinical studies, the oral bioavailability of small molecule drugs in humans and rodents have demonstrated poor correlation80.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Hatton, G. B., Yadav, V., Basit, A. W. & Merchant, H. A. Animal farm: considerations in animal gastrointestinal physiology and relevance to drug delivery in humans. J. Pharm. Sci. 104, 2747–2776 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chowdhury et al. engineered a non-pathogenic E. coli strain to lyse specifically within the tumor microenvironment and release an anti-CD47 antagonist nanobody; the authors demonstrated activation of tumor-infiltrating T cells, tumor regression, and long-term survival in a syngeneic tumor model in mice, as well as abscopal effects on untreated tumors.

    “In another report, Chowdhury et al. engineered a non-pathogenic E. coli strain to lyse specifically within the tumor microenvironment and release an anti-CD47 antagonist nanobody. The authors demonstrated the activation of tumor-infiltrating T cells, tumor regression, and long-term survival in a syngeneic tumor model in mice, as well as abscopal effects on untreated tumors15.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Chowdhury, S. et al. Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nat. Med. 25, 1057–1063 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Quantitative systems pharmacology approaches have been widely used to accelerate drug development for other modalities, including small molecules and recombinant proteins, by modeling the pharmacokinetic and pharmacodynamic properties of drug candidates across a wide assortment of therapeutic indications.

    “Quantitative systems pharmacology approaches have been widely used to accelerate drug development for other modalities, including small molecules and recombinant proteins, by modeling the pharmacokinetic and pharmacodynamic properties of drug candidates across a wide assortment of therapeutic indications82.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Milligan, P. A. et al. Model-based drug development: a rational approach to efficiently accelerate drug development. Clin. Pharmacol. Ther. 93, 502–514 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Zhang et al. developed a strain of EcN to express azurin, a small bacterial protein that induces apoptosis in tumor cells; this engineered strain suppressed the growth of tumors and prevented pulmonary metastasis in mice.

    “Zhang et al. developed a strain of EcN to express azurin, a small bacterial protein that induces apoptosis in tumor cells62. This engineered strain suppressed the growth of tumors and prevented pulmonary metastasis in mice63.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [62] Yamada, T. et al. Apoptosis or growth arrest: modulation of tumor suppressor p53’s specificity by bacterial redox protein azurin. Proc. Natl Acad. Sci. USA 101, 4770–4775 (2004). source

      Not checked in the free run.

    • cites [63] Zhang, Y. et al. Escherichia coli Nissle 1917 targets and restrains mouse B16 Melanoma and 4T1 breast tumors through expression of Azurin protein. Appl. Environ. Microbiol. 78, 7603–7610 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ho et al. engineered EcN for the treatment of colorectal cancer by expressing HlpA, a protein that binds specifically to a heparan sulphate proteoglycan, enabling engineered EcN to specifically target polyps in a murine colorectal cancer model.

    “More recently, Ho et al. engineered EcN for the treatment of colorectal cancer by expressing HlpA, a protein that binds specifically to a heparan sulphate proteoglycan, enabling engineered EcN to specifically target polyps in a murine colorectal cancer model65.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Ho, C. L. et al. Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention. Nat. Biomed. Eng. 2, 27–37 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    Engineered live biotherapeutic products have the potential for delivering a living medicine that can sense signals within the patient, respond at the site of disease, and alleviate concerns of systemic exposure and toxicity.

    “Engineered LBPs have the potential for delivering a living medicine that can sense signals within the patient, respond at the site of disease, and alleviate concerns of systemic exposure and toxicity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    Assessment of viability using commercial live/dead stains to detect intact cell membranes may be more appropriate for enumerating VBNC cells in the drug product.

    “In this case, assessment of viability using commercial live/dead stains to detect intact cell membranes may be more appropriate for enumerating cells in the drug product88.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Boulos, L., Prévost, M., Barbeau, B., Coallier, J. & Desjardins, R. LIVE/DEAD® BacLightTM: application of a new rapid staining method for direct enumeration of viable and total bacteria in drinking water. J. Microbiol. Methods 37, 77–86 (1999). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The field will be greatly advanced by the first proof of concept demonstration of an engineered bacterial therapeutic delivering a clinically meaningful impact on disease in patients.

    “Since no recombinant LBPs have been approved for use in humans, the field will be greatly advanced by the first proof of concept demonstration of an engineered bacterial therapeutic delivering a clinically meaningful impact on disease in patients.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: No recombinant live biotherapeutic products have been approved for use in humans.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    Longer-term colonization by live bacterial therapeutics in the gastrointestinal tract may allow continuous delivery of a therapeutic effector, reducing the need for repeat dosing and enabling lower efficacious bacterial dose levels.

    “However, it may be desirable to establish longer-term colonization by live bacterial therapeutics in the gastrointestinal tract44 to allow for continuous delivery of a therapeutic effector, thereby reducing the need for repeat dosing and enabling lower efficacious bacterial dose levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Shepherd, E. S., DeLoache, W. C., Pruss, K. M., Whitaker, W. R. & Sonnenburg, J. L. An exclusive metabolic niche enables strain engraftment in the gut microbiota. Nature 557, 434–438 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Expansion of the tools for synthetic biology to allow commensal organisms to be considered as chassis for engineered bacterial therapeutics could enhance compatibility of the strain with the human host.

    “Finally, expansion of the tools for synthetic biology, to allow commensal organisms to be considered as chassis for engineered bacterial therapeutics, could enhance compatibility of the strain with the human host.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Current bacterial synthetic biology tools are most advanced for strains of E. coli and Lactobacillus, but there are comparatively few engineering tools for the diverse set of strict anaerobes that reside in the colon.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    Odor and color masking may be needed for any live biotherapeutic product to ensure patient compliance.

    “Odor and color masking may also be needed for any LBP to ensure patient compliance93.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Tan, X., Feldman, S. R., Chang, J. & Balkrishnan, R. Topical drug delivery systems in dermatology: a review of patient adherence issues. Expert Opin. Drug Deliv. 9, 1263–1271 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Technological advances including microencapsulation and cryoprotectants could improve the stability of future live biotherapeutic product formulations.

    “Technological advances including microencapsulation and cryoprotectants could improve the stability of future LBP formulations90,91, and buffering may be considered to preserve cell activity and viability in the stomach.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [90] Yus, C. et al. Targeted release of probiotics from enteric microparticulated formulations. Polymers 11, 1668 (2019). source

      Not checked in the free run.

    • cites [91] Guowei, S. et al. Comprehensive optimization of composite cryoprotectant for Saccharomyces boulardii during freeze-drying and evaluation of its storage stability. Prep. Biochem. Biotechnol. 49, 846–857 (2019). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Engineered microbes could act as biological thermostats and synthesize therapeutic effectors only as needed.

    “In other words, engineered microbes could act as biological thermostats and synthesize therapeutic effectors only as needed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Formulations that require frozen storage and at-home reconstitution present challenges for patients, potentially leading to compliance issues and risks of product instability.

    “However, for outpatient studies, formulations that require frozen storage and at-home reconstitution present challenges for patients, potentially leading to compliance issues89 and risks of product instability.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Shahiwala, A. Formulation approaches in enhancement of patient compliance to oral drug therapy. Expert Opin. Drug Deliv. 8, 1521–1529 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Live biotherapeutic product formulations must be palatable to patients to ensure compliance with dosing.

    “LBP formulations must also be palatable to patients to ensure compliance with dosing89.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Shahiwala, A. Formulation approaches in enhancement of patient compliance to oral drug therapy. Expert Opin. Drug Deliv. 8, 1521–1529 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Predicting the translational potential of engineered bacterial therapeutics necessitates a move toward mathematical frameworks for integrating data from in vitro and in vivo model systems to predict the behavior of engineered strains in dynamic host conditions.

    “Predicting the translational potential of engineered bacterial therapeutics necessitates a move toward mathematical frameworks for integrating data from in vitro and in vivo model systems to predict the behavior of engineered strains in these dynamic conditions.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The function of engineered biotherapeutic strains in the host environment is a complex, dynamic system.
    • Rests on an assumption: In oral administration of an engineered organism, strain activity is a function of gastric emptying, changing intestinal pH, oxygen and nutrient availability, strain viability, and dose.

  • May combine two claims.

    Premisecitation

    Hydrogel formulations have been used for delivery of intratumoral drugs and may improve the concentration of the live biotherapeutic product within the tumor.

    “Hydrogel formulations have also been used for delivery of intratumoral drugs and may improve the concentration of the LBP within the tumor92.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Fakhari, A. & Anand Subramony, J. Engineered in-situ depot-forming hydrogels for intratumoral drug delivery. J. Control. Release 220, 465–475 (2015). source

      Not checked in the free run.

51 of 51

  • The paper relies on this without support.

    Many diseases that represent a substantial unmet medical need are underlain by a complex interplay of metabolic and immunological mechanisms.

    “A complex interplay of metabolic and immunological mechanisms underlies many diseases that represent a substantial unmet medical need.”

  • The paper relies on this without support.

    The FDA has not approved a live biotherapeutic product for medicinal use to date.

    “the FDA has not approved a live biotherapeutic product for medicinal use to date.”

  • The paper relies on this without support.

    There is no published guidance that outlines toxicology requirements for LBPs specifically.

    “Since there is no published guidance that outlines toxicology requirements for LBPs specifically”

  • The paper relies on this without support.

    The specific requirements for development of engineered live bacterial therapeutics in the European Union remain to be defined and may differ from those in the United States.

    “The specific requirements for development of engineered live bacterial therapeutics in the European Union remain to be defined and may differ from those in the United States.”

  • The paper relies on this without support.

    Solid tumors display abnormal blood vessel architecture, resulting in the development of hypoxic regions and a necrotic core that can serve as suitable habitats for obligate and facultative anaerobic bacteria.

    “Solid tumors display abnormal blood vessel architecture, resulting in the development of hypoxic regions and a necrotic core that can serve as suitable habitats for obligate and facultative anaerobic bacteria.”

  • The paper relies on this without support.

    Environmental conditions, including pH, oxygen concentration, and nutrient availability, are major determinants of strain viability and metabolism.

    “Environmental conditions, including pH, oxygen concentration, and nutrient availability, are major determinants of strain viability and metabolism”

  • The paper relies on this without support.

    The function of engineered biotherapeutic strains in the host environment is a complex, dynamic system.

    “The function of engineered biotherapeutic strains in the host environment represents a complex, dynamic system.”

  • The paper relies on this without support.

    In oral administration of an engineered organism, strain activity is a function of gastric emptying, changing intestinal pH, oxygen and nutrient availability, strain viability, and dose.

    “In the case of oral administration of an engineered organism, strain activity is a function of gastric emptying, changing intestinal pH, oxygen and nutrient availability, strain viability, and dose.”

  • The paper relies on this without support.

    The absence of quantitative biomarkers severely limits the information available to investigators about the function of an engineered live bacterial therapeutic in humans prior to efficacy studies in patients.

    “Conversely, the absence of quantitative biomarkers can severely limit the information available to investigators about the function of an engineered live bacterial therapeutic in humans prior to efficacy studies in patients.”

  • The paper relies on this without support.

    The scale of manufacturing necessary for bacterial therapeutics is determined largely by dosing requirements, and the efficacious dose of an engineered bacterial strain depends on both its encoded mechanism of action and its route of administration.

    “The scale of manufacturing that is necessary for bacterial therapeutics will be determined largely by dosing requirements, and the efficacious dose of an engineered bacterial strain, in turn, is likely to be dependent on both its encoded mechanism of action and its route of administration.”

  • The paper relies on this without support.

    The inclusion of engineered genetic circuits encoding novel effector functions may come at a cost to bacterial fitness and/or growth rates, leading to selective pressure for strain variants that have lost the engineered function and its associated fitness costs.

    “The inclusion of engineered genetic circuits encoding novel effector functions may come at a cost to bacterial fitness and/or growth rates, and this can lead to selective pressure for strain variants that have lost the engineered function and its associated fitness costs.”

  • The paper relies on this without support.

    A quantifiable relationship between the effectors expressed by an engineered organism and the underlying mechanisms of disease is necessary in order to engineer an optimal strain.

    “A quantifiable relationship between the effectors expressed by an engineered organism and the underlying mechanisms of disease is necessary in order to engineer an optimal strain, but there remains a paucity of disease- and effector-related biomarkers to establish dose-response relationships, as well as target engagement at the site of action.”

  • The paper relies on this without support.

    There remains a paucity of disease- and effector-related biomarkers to establish dose-response relationships and target engagement at the site of action.

    “A quantifiable relationship between the effectors expressed by an engineered organism and the underlying mechanisms of disease is necessary in order to engineer an optimal strain, but there remains a paucity of disease- and effector-related biomarkers to establish dose-response relationships, as well as target engagement at the site of action.”

  • The paper relies on this without support.

    Current bacterial synthetic biology tools are most advanced for strains of E. coli and Lactobacillus, but there are comparatively few engineering tools for the diverse set of strict anaerobes that reside in the colon.

    “Current bacterial synthetic biology tools are most advanced for strains of E. coli and Lactobacillus, but there are comparatively few engineering tools for the diverse set of strict anaerobes that reside in the colon.”

  • The paper relies on this without support.

    No recombinant live biotherapeutic products have been approved for use in humans.

    “Since no recombinant LBPs have been approved for use in humans, the field will be greatly advanced by the first proof of concept demonstration of an engineered bacterial therapeutic delivering a clinically meaningful impact on disease in patients.”
15 of 15

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Bacterial cancer therapy faces substantial regulatory hurdles and has not yet achieved commercial approval despite ongoing trials.

    “Regulatory challenges for BCT agents are considerable (Fig. 5A), and despite ongoing clinical trials (e.g. NCT04167137), they have yet to be commercially surmounted (151).”

    From The microbiome and human cancer (2021) · cites this paper as [151]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Table lists only two ActoBio-sponsored Lactococcus candidates

    Minor

    The text says Acto Bio Therapeutics has three candidates in clinical development, but Table 1 attributes only AG014 and AG019 to ActoBio; it attributes the third Lactococcus lactis candidate, AG013, to Oragenics.

  • Discontinued therapeutic appears in clinical-development table

    Minor

    Table 1 is described as a list of therapeutics currently in clinical development, but its SYNB1020 row says development was discontinued.

2 of 2

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. Deal, C. Science and Regulation of Live Microbiome-Based Products Used to Prevent, Treat, or Cure Diseases in Humans - 09/17/2018 - 09/17/2018. (U.S. Food and Drug Administration, 2019). http://www.fda.gov/vaccines-blood-biologics/workshops-meetings-conferences-biologics/science-and-regulation-live-microbiome-based-products-used-prevent-treat-or-cure-diseases-humans.

Cited by

Sorted by citations

Related

Authors
Charbonneau, M. R., Isabella, V. M., Li, N., & Kurtz, C. B.
Affiliations
Synlogic (United States) (US)
Corresponding author
Kurtz, Caroline B.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-04-08
Volume
11
Issue
1
Pages
1738-1738
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-15508-1
PMC
PMC7142098
OpenAlex
W3015470929
Semantic Scholar
fd09d1caf6d781e75ee50298036a345bc462225d
Cited by
523
References
93
Citations by year
2026: 118 · 2025: 114 · 2024: 78 · 2023: 61 · 2022: 68 · 2021: 64 · 2020: 18 · 2017: 1
FWCI
5.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
Keywords
live biotherapeutic products, synthetic biology, non-pathogenic bacteria, metabolic disorders, immune disorders, regulatory considerations, patient acceptance
MeSH terms
Bacteria, Disease, Genetic Engineering, Humans, Neoplasms, Biomarkers, Gastrointestinal Tract

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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