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This project is one of the five winners of the call 2016 «Microbials – Direct Use of Micro-Organisms».
Project partners: EPFL, Global Health Institute, Lausanne
Project no: GRS-057/16
Amount of funding: CHF 374'000
Duration: 05.2017 - 04.2020
Area of activity: Microbials, seit 2016
Dr. Alexandre Persat
Ecole Polytechnique Fédérale de Lausanne
Global Health Institute, School of Life Sciences
EPFL SV GHI, Station 19
1015 Lausanne (Schweiz)
- alexandre.persat@epfl. ch
With the advent of genome engineering and synthetic biology, we can now optimize and assemble sensing and effecting systems into cellular machines that perform a variety of complex tasks in a defined context. Consequently, engineering and programming bacteria into “smart therapeutics” that patrol a host to detect and treat diseases now appears as a realistic endeavor. Such strategies may help us treat a variety of conditions including cancer, infectious diseases or immune disorders.
However, a major obstacle in developing successful bacterial therapies is the lack of specificity of their action as they may target both healthy and sick tissues. Here, we propose to design and engineer a mechanosensitive bacterial therapy (mBaT), a specific contact-dependent bacterial cargo system able to inject DNA and helper proteins into host cells. We aim to specifically test our system in monogenic diseases models in vitro. To achieve this, we will assemble multiple sensing and effecting components allowing a bacterium to identify and inject therapeutic DNA and helper proteins into target cells. The DNA will encode for the state of the art gene editing machinery CRISPR-Cas9, allowing fixing the causative mutation at the single base-pair level. Altogether, mBaTs will constitute the first proof of concept for bacterial-based DNA delivery for the targeted treatment of genetic disorders.
What is special about the project?
With mBaTs, our hope is to provide a more targeted DNA delivery of the gene editing machinery. Unlike adeno-associated viruses, bacteria have the ability to transfer DNA sequences long enough to encode the gene editing machinery, navigate within tissue and be engineered with adhesins to bind to specific biomarkers. A biomarker-specific mechanosensitive bacterial treatment could thus provide a fully autonomous gene editing treatment system without side effects.
mBaTs will potentially provide a new tool for a broad range of applications. In the future we plan on further developing these as a general cargo system that can deliver therapeutic DNA in a variety of disease models. For example, refining adhesin components will allow for the search of lung cells harboring the mutation causing cystic fibrosis. Similarly, we can anticipate that mBaT can target any type of cell or tissue with distinctive biochemical surface signature such as cancer cells: in this case, the injection of “suicide gene” may allow for targeted tumour eradication. Finally, mBaTs provide a new tool to the synthetic biology community by providing a system that responds to the mechanics of the environment.
We developed a synthetic scaffold for the display of adhesins at the surface of Agrobacterium tumefaciens, a plant pathogen we are rewiring for the DNA delivery in human cells. A proof-of-concept experiment demonstrates a strong binding of A. tumefaciens to human and yeast cells, for which it usually has little affinity.
We are broadening the nature of the adhesive display to allow for the binding to multiple different biomarkers such as sugars present on surface of different cell types.
None so far
None so far
Persons involved in the project
Last update to this project presentation 22.02.2019