Phages and Phage4Cure in the media

Here are some media tips: As part of the documentary series “plan b”, the German TV station ZDF featured a report on bacteriophages on 03. November 2018, in which the scientists of the project Phage4Cure were interviewed as well. The video is available here until 03. November 2019:

 

Update of Leibniz-Institut DSMZ GmbH and Fraunhofer ITEM

At Leibniz-Institut DSMZ GmbH, phage screening was successfully completed. Since the beginning of the project, it has been the basis for all subsequent steps of the project and has led to a selection of promising phage species, which in combination show a comparatively high bacterial host coverage of Pseudomonas aeruginosa strains.

Detailed investigation of many different phages with regard to their efficiency in destroying the host bacteria and many other aspects finally narrowed the circle of possible candidates for further processing by ITEM. Basically, it was desired that the phages would complement each other significantly in their bacterial coverage in order to increase the final coverage percentage of patient strains in the clinical application. On the other hand, it was desired that the phages overlap in their bacterial coverage so that more than one phage can effectively attack patient strains as often as possible.

Phage-lab, (C) Chr. Rohde

Such forward-looking considerations and, in addition, the greatest possible genetic and morphological diversity of phage contribute significantly to the efficiency of the final phage product and are based on the biology of the individual phage. Therefore, phages for clinical application must be comprehensively investigated and compared, always with the aim of successful high purification. Consequently, they must also produce high titres, be stable in the event of slight temperature or pH fluctuations, remain stable in the planned application form, etc.

The fact that these factors are present in many phages is due to the fortunate circumstance of evolution: Phages are the most common living units on earth, ensure the continuous turnover of one third of the global bacterial mass and live as a regulatory force in our own microbiome. In the meantime, three different phages have been selected as candidates and were handed over to ITEM for reproduction.

During the further course of the project, Leibniz Institute DSMZ GmbH will continue to work on the characterisation of these phages in order to learn more about the three phages with regard to their effectiveness as phage “cocktails” in comparison to the effect of antibiotics or about their effectiveness in artificial biofilms or artificial sputum medium.

Immediately after receipt of the phages, the multi-stage, complex sequence of production steps for the propagation and purification of these three candidates began at the Fraunhofer Institute ITEM. At the moment, the research group is trying to optimize the purification process.

At a recent meeting of the project participants in Berlin, the toxicological programme of the pre-clinic was coordinated. The aim is to ensure that, as far as possible, future project phases are harmonised between the partners at an early stage and adapted to regulatory requirements, so that the preclinical development work can be tackled in a timely manner as soon as phage material is available from ITEM.

Coordination with the regulatory authorities

The long-term perspective of the joint project Phage4Cure is the approval of bacteriophages for the treatment of bacterial infections. Although bacteriophages have been used as therapy for more than one hundred years, there are many different aspects to be considered when compared with traditional drugs. Until now, drug approval procedures have been based on classical chemical and biotechnological substances and can therefore not simply be translated to phages. In order to pave the way for the approval of phage therapy, the project members aim to discuss the necessary steps regularly with the regulatory authorities. Already at the end of September 2017, the Paul Ehrlich Institute (PEI) hosted a meeting in Langen near Frankfurt. In February 2018 the first meeting took place at the Federal Institute for Drugs and Medical Devices (BfArM) in Bonn. Meanwhile, the responsibility of the authorities has been clarified: the BfArM will be in charge.

The project team visiting the BfArM (Febr. 2018) F.l.t.r.: Prof. Dasenbrock (ITEM), Dr. Rohde (DSMZ), Dr. Hüser (CRO), Dr. Roß (ITEM), Dr. Hertrampf (CRO), Fr. Lehmann (CRO), Dr. Ziehr (ITEM), Prof. Witzenrath (Charité)
The project team visiting the PEI (Sept. 2017) F.l.t.r.: Dr. Rohde (DSMZ), Dr. Uhle (CRO), Dr. Hertrampf (CRO), Dr. Seitz (ITEM), Prof. Witzenrath (Charité), Prof. Dasenbrock (ITEM), Dr. Ziehr (ITEM), Dr. Roß (ITEM), Dr. Hüser (CRO).

Interim report of the DSMZ laboratory

The first stage „selection of phages“ within the joint project „Phage4Cure“ consists of the targeted search for bacteriophages, their clonal purification, characterization, comparison, propagation and appropriation for further pharmaceutical development. These steps form the essential phage biology in the initial part of the project. Aim of this joint project is to prepare a variety of phages, that complement one another in terms of their host spectrum; as antiinfective agents against the multiresistant bacterium Pseudomonas aeruginosa.

Electron-microscopical shot of pseudomonads with docked bacteriophages. Copyright M. Rohde, HZI

During this process a great variety of Pseudomonas phages will be tested for their effectiveness against a broad spectrum of Pseudomonas strains. These bacterial strains were isolated from a variety of patients in international clinics. Phages are now met with the challenge to win the fight against multiresistant bacteria after the failure of antibiotics. The most difficult aspect of phage biology is the physicochemical receptor recognition of phages when coming into contact with bacterial surfaces. The effectiveness of this highly specific ability of each phage to bind with the bacteria ultimately leads to the destruction of the bacteria.

Since the start of the project the screening of phages in the laboratories of Leibniz-Institut DSMZ GmbH has already produced some promising results. Quantitative comparison of phage efficiency, morphology, and genetic make-up have produced evaluation patterns that represent the next milestone for Phage4Cure. This will be the selection of the therapeutically most effective phages for transfer to Fraunhofer ITEM where a production procedure for the growth and purification of the phages will be put into place. Ultimately this reproducible procedure should produce pharmaceutically pure phages that can then be used in the next steps of the project.