Application of a commensal gut bacterium for the controlled delivery of heterologous proteins to the lower GI tract
Lead Research Organisation:
University of East Anglia
Department Name: Norwich Medical School
Abstract
Oral administration is the preferred route for delivering therapeutic proteins to the gut. To be effective, significant obstacles including minimising loss of activity during transit and controlling the dose delivered must be overcome. Our technology is designed to overcome these obstacles and uses the human commensal gut bacterium, Bacteroides ovatus (Bo) to deliver therapeutic agents in the gut in response to the dietary plant based sugar, xylan. This drug delivery platform technology will be further developed using a characterised model Bo strain producing a potent anti-inflammatory agent that can effectively treat and prevent gut inflammation. Determining optimal dosing and delivery regimens and the impact of Bo and xylan dosing on resident gut bacteria and demonstrating functionality in the large bowel will achieve this. The final output will be a robustly characterised delivery technology with pre-clinical proof of safety and functionality for the delivery of therapeutic proteins
Publications
Aktar R
(2020)
Human resident gut microbe Bacteroides thetaiotaomicron regulates colonic neuronal innervation and neurogenic function.
in Gut microbes
Carvalho AL
(2019)
Bioengineering commensal bacteria-derived outer membrane vesicles for delivery of biologics to the gastrointestinal and respiratory tract.
in Journal of extracellular vesicles
Carvalho AL
(2019)
Use of bioengineered human commensal gut bacteria-derived microvesicles for mucosal plague vaccine delivery and immunization.
in Clinical and experimental immunology
Fonseca S
(2024)
Corrigendum: Extracellular vesicles produced by the human gut commensal bacterium Bacteroides thetaiotaomicron elicit anti-inflammatory responses from innate immune cells
in Frontiers in Microbiology
Horn N
(2016)
A Novel Tightly Regulated Gene Expression System for the Human Intestinal Symbiont Bacteroides thetaiotaomicron.
in Frontiers in microbiology
Jones EJ
(2020)
The Uptake, Trafficking, and Biodistribution of Bacteroides thetaiotaomicron Generated Outer Membrane Vesicles.
in Frontiers in microbiology
Juodeikis R
(2024)
Differential temporal release and lipoprotein loading in B. thetaiotaomicron bacterial extracellular vesicles.
in Journal of extracellular vesicles
| Description | Live bacteria cannot be used as drug delivery vehicles in humans due to genetic exchange and the reciprocal transfer of genes to and from the genetically engineered bacterium to other gut commensal bacteria. The extent of genetic exchange is considerable as demonstrated by the transfer and exchange of not only "marker" genes but also other unrelated and more distant genes within the chromosome of the GM-bacterium to other bacteria in the intestinal microbiota. Based upon the close similarity of the genetic makeup and process of genetic exchange amongst a wide range of commensal bacteria that are currently being used as GM-bacterial drug delivery vehicles we feel that the process of genetic exchange we have described in commensal Bacteroides spp. is applicable to other bacteria and in particular, Lactococcus app. that are being used in human trials. |
| Exploitation Route | They represent a word of caution to others interested in developing and using live bacteria to deliver therapeutic agents to patients or any other animal species. |
| Sectors | Agriculture Food and Drink Healthcare Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
| Description | Public engagement activities including IFR in the City seminars. Discussions with commercial biopharmaceutical companies for additional investment/sponsorship of the research. New IP has also emerged from the work. As a result of this work an alternate, non-viable, bacterial product-based drug delivery technology has been developed. This technology utilises extracellular vesicles natural produced by Gram negative bacteria in the gut that can permeate the epithelial barrier and access underlying immune cells and the vasculature. The genetic tools produced during this project have been used to engineer commensal gut bacteria to express heterologous proteins in their extracellular vesicles. Current applications of this technology include therapeutic protein delivery to the inflamed gut and intranasal vaccine delivery for respiratory virus infection, including influenza and SARS-CoV-2. |
| First Year Of Impact | 2018 |
| Sector | Healthcare,Manufacturing, including Industrial Biotechology |
| Impact Types | Economic |
| Description | An OMV-based SARS-CoV-2 (COVID-19) mucosal vaccine technology platform |
| Amount | £10,000 (GBP) |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 12/2020 |
| End | 04/2021 |
| Description | An OMV-based SARS-CoV-2 (COVID-19) mucosal vaccine technology platform |
| Amount | £10,000 (GBP) |
| Funding ID | BB/S506679/1 |
| Organisation | Quadram Institute Bioscience |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 12/2021 |
| End | 04/2022 |
| Description | CARDING_Q20CASE: The gut microbiome and inflammaging |
| Amount | £150,000 (GBP) |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2020 |
| End | 09/2024 |
| Description | Vaccines for Global Development - Preclinical |
| Amount | £500,000 (GBP) |
| Organisation | Innovate UK |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2017 |
| End | 04/2018 |
| Description | Collaboration with School Biosciences Univ. Kent |
| Organisation | University of Kent |
| Country | United Kingdom |
| PI Contribution | Production of bacterial extracellular vesicles (BEVs) for mucosal vaccine antigen delivery; purification, biophysical/biochemical/immunological characterisation and pre-clinical testing of vaccine formulations. |
| Collaborator Contribution | Expertise in production and modification of recombinant viral protein antigens for conjugating to BEVs for pre-clinical evaluation. |
| Impact | UKRI, Innovate UK grant applications to develop the technology for first in man studies. BBSRC Discovery Fellowship application by UoK investigator |
| Start Year | 2020 |
| Description | Eastern ARC |
| Organisation | University of Kent |
| Country | United Kingdom |
| PI Contribution | Refinement of bacterial extracellular microvesicle (BEV) based drug/vaccine delivery technology; evaluation of vaccine formulations for COVID-19 |
| Collaborator Contribution | Provision of recombinant viral proteins and means of complexing with BEVs |
| Impact | No outputs to date. Multidisciplinary- molecular microbiology, protein chemistry, bioengineering, animal biology |
| Start Year | 2020 |
| Description | Mucosal vaccines |
| Organisation | University of Liverpool |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Production and characterisation of native and engineered bacterial extracellular vesicles for pre-clinical testing |
| Collaborator Contribution | Use of rodent models of viral (influenza, SARS-CoV-2) infection to evaluate efficacy and safety of BEV vaccine formulations |
| Impact | UKRI grant applications to further develop BEV drug delivery technology for first in man studies |
| Start Year | 2019 |
| Description | NuAGE |
| Organisation | University of Bologna |
| Country | Italy |
| Sector | Academic/University |
| PI Contribution | Partner and recruiting site for dietary intervention in the elderly study funded by EU and led by Bologna Univ. (Prof Claudio Franchesci) |
| Collaborator Contribution | Work Package leader responsible for undertaking blood-based immune profiling and characterisation on participant samples pre- and post-intervention |
| Impact | Clements, SJ and SR Carding. 2015. Can nutritional intervention counteract immunosenescence in the elderly? In: Molecular Basis of Nutrition and Aging. (Ed. M. Malavolta, E. Mocchegiani) Elsevier. 28:375-392. Clements, SJ, and SR. Carding. 2016. Diet, the intestinal microbiota and immune health in ageing. Crit. Rev. Food Sci. & Nutr. 10:1-11 Clements, S., Maijo, M., Ivory, K., Nicoletti, C, SR Carding. 2017. Age associated decline in dendritic cell function and the impact of Mediterranean diet intervention in elderly subjects. Front. Nutri. 4:65. Maijo, M., K. Ivory, S. Clements, J. Dainty, A. Jennings, J. Gillings, S. Fairweather-Tait, M. Gulisano, A. Santoro, C. Franceschi, SR. Carding, C Nicolett. 2018. One-Year Consumption of a Mediterranean-Like Dietary Pattern With Vitamin D3 Supplements Induced Small Scale but Extensive Changes of Immune Cell Phenotype, Co-receptor Expression and Innate Immune Responses in Healthy elderly individuals. Front. Physiol. 9:997. |
| Start Year | 2010 |
| Title | Medium Production of Bacterial Extracellular Vesicles |
| Description | The present invention relates to a growth medium or media and the use and/or manufacture thereof for the production of bacterial extracellular vesicles. |
| IP Reference | 2102001.1 |
| Protection | Patent application published |
| Year Protection Granted | 2021 |
| Licensed | No |
| Impact | None as yet. Patent filed 12 Feb. 2021 |
| Title | Microvesicle mediated drug delivery platform technology |
| Description | Engineering of major human commensal gut bacterium for incorporating heterologous proteins into their out membrane vesicles for delivery to the GIT |
| IP Reference | |
| Protection | Patent application published |
| Year Protection Granted | 2017 |
| Licensed | No |
| Impact | None to date |