Prædiktive 3D cellemodeller

Senest opdateret d. 13/4-2018
Resultatkontrakt 2019-2020 under temaerne Sundhed og medicoteknologi
Bjørn Holst
R&D Manager, Disease Models

Komplekse datasæt er af afgørende betydning for sygdomsforståelse og den senere godkendelse af nye lægemiddelstoffer. Knowhow inden for 3D in vitro modeller, herunder 3D printning, vil kunne hjælpe danske virksomheder med at imødekomme dette behov.

En markant øget efterspørgsel efter prækliniske data i forbindelse med udviklingen af nye lægemiddelstoffer og bedre sygdomsforståelse, kræver velunderbyggede prædiktive in vitro modeller, der i højere grad afspejler den enkelte sygdom. Den foreslåede aktivitet vil imødekomme dette behov ved, at opbygge og udbyde serviceydelser omkring teknologier til opbygning af 3D in vitro modeller, herunder 3D bioprinting (Forsk2025).


17 kommentarer

Herunder er indlæg og kommentarer fra interessenter på aktiviteter og aktivitetsforslag.

Uwe Hermann (Senior Drector and Head of Research, Eriksholm Research Center)
Onsdag d. 18/4-18 kl. 10:45

Thank you! - That si a very good initiative!
In hearing healthcare related research 3D cell-models will have increasing importance in different fields.
One field is the development of drugs which can target e.g. the loss of haircells in the Cochlea or the repair of damages in the auditory nerve.
Additionally 3d models of cells inside the Cochlea will be instrumental for the understanding of the complex functions of the Cochlea and potential targets for future research in regenerative medicine.

Kenneth Petersen (CEO, Hoba Therapeutics)
Fredag d. 20/4-18 kl. 11:08

A very interesting and needed proposal.
In the spectrum of degenerative CNS disorders (e.g. dementia and Parkinson's disease) the underlying disease mechanisms and causes are complex and poorly understood. 3D cell-models could be an important tool, not only in elucidating the pathology but also in the identification of novel targets for treatment options. Especially, when developing drugs for brain disorders early understanding of the safety profile is important and the use of 3D modeling could be very beneficial both in regard to time and money.
I hope you will be successful in implementing the technology, which I hope to take advantage of in the near future

Poul Hyttel (Professor, University of Copenhagen)
Fredag d. 20/4-18 kl. 13:34

As Director of the Stem Cell Center of Excellence in Neurology, BrainStem, I fully support the idea of building more complex 3D modeling ressources. BrainStem was launched in 2015 with the ultimate goal of developing a platform for modeling of neurodegenerative disorders based on the use of patient-specific induced pluripotent stem cells (iPSCs). We have established multiple iPSC lines from patients suffering from Alzheimer’s disease, fronto-temporal dementia and spinocerebellar ataxia. Moreover, for the familial disease forms we have established CRISPR/Cas9 gene edited control cell lines and we have, furthermore, used the gene editing technology for introduction of disease-causing mutations in neutral cell lines. Importantly, we have clearly demonstrated the proof-of-principle by identification of known and novel disease phenotypes in the neural in vitro cell models. We are, however, also fully aware that our 2D in vitro models miss the complexity of the brain and fall short in demonstration of more composed disease phenotypes. It would therefore be a great asset for BrainStem to collaborate with Bioneer in the area of 3D modeling for capturing a more complete range of phenotypes.

Itedale Namro Redwan (Scientific Officer/Senior Principal Scientist, CELLINK, BITE R&D)
Tirsdag d. 1/5-18 kl. 17:09

This is indeed a very important project which if granted will lead to important contributions to the future of medicine and scientific research. As a representative from CELLINK in Sweden, I believe the more efforts are required in the field of creating relaible 3D cell models. 3D bioprinting, although still at its infancy, is an excellent technology with enormous potential. 3D bioprinted tissue models can be made with multiple cells types (eg. primary cells) at specific locations within the tissue model. Not only that, but this tissue model can be printed in any wellplate format, depending on the desired size. Hence, this gives scientists the possibility to design and bioprint more complex tissue models that was previously possible with other technologies. Such complex 3D tissue models can be utilized in the early drug development process as in vitro screening platform for safety and toxicity studies (eg. liver toxicity models, drug-induced liver injury models), as well as to asses the functionality of a tissue/organ model after exposing the 3D model to different compounds. Once the complex 3D tissue model is printed, this can be cultured in the incubator, either in static conditions (e.g. petridish, wellplate) or in dynamic conditions (e.g. bioreactors) to expose the cells to a more physiologically relevant environment. The bioprinted tissue models can be cultured for days, weeks or months, depending on the assay or the degree of maturation required before testing. Since all of this happens in a lab environment, the cost for maintaining the in vitro 3D cell culture is much more cost effective than performing an in vivo study, not to mention the complications involved and sometimes inconclusive results obtained from animal studies.
As one of the world leaders in 3D bioprinter and bioink providers, we support this project and see a huge potential for fruitful collaborations with Bioneer.

Tina Stummann (PhD, H. Lundbeck)
Torsdag d. 3/5-18 kl. 07:52

There is a strong need for strongly predictive in vitro models in pharmaceutical research. Recent publications on organoid systems indicate that the three-dimensional cell- to-cell interaction creates more physiological relevant cell environments than traditional 2D culturing and have therefore raised great exceptions to these models for improving in vitro to in vivo translation. There is therefore an urgent need for development of quantitative endpoints and evaluation of predictivity of 3D models within several disease areas. Bioneer’s initiative therefore covers a highly important but unmet need. Successful development of immunological and lever models would create knowhow on the 3D cell culture technology. I anticipate that such knowledge would feed into other important disease area as e.g. neurodegeneration. Overall, the proposal has great potential for impacting future medical research strategies.

Christian Honore (Senior Scientist, Novo Nordisk A/S)
Torsdag d. 3/5-18 kl. 20:03

I think this is a very good initiative towards addressing a significant problem in drug development. There is a high attrition rate in drug development and finding ways of better predicting efficacy and safety of drugs during early stages of development could be very beneficial for the pharmaceutical industry. Being able to generate 3D models (e.g. organoids) that captures the complexity of tissues, rather than using 2D culture formats and single cell lines, could be aid such efforts. Studies have shown that organoids representing various tissues, such as the brain, intestine and liver can be generated, thus providing proof of concept. The next step will be to develop these complex 3D models into standardized formats amenable for the need of the pharmaceutical industry. I fully support Bioneers initiative and feel that it could help provide better predictive models for efficacy and safety useful for drug development.

Anne Marie Vinggaard (Professor, DTU)
Tirsdag d. 8/5-18 kl. 13:43

I can fully support this initiative and all the positive comments. We really need good 3D cell models for evaluating safety of drugs and environmental chemicals which are better in predicting human safety than the present rodent studies. This will result in improved risk assessments of chemicals and drugs to the benefit of future generations.

Mikkel Pedersen (Director, Symphogen)
Tirsdag d. 8/5-18 kl. 14:12

There is no doubt that 3D models are the future for in vitro drug discovery and drug development. Organoids derived directly from primary human tissues maintain many of the genetic and phenotypic characteristics of the tissue from which they were derived. Tumor organoids for example have recently been demonstrated to be able to predict drug responses in human phase 1/2 clinical trials in heavily pretreated colorectal and gastroesophageal cancer patients. Performing “in vitro” trials using tumor organoids during the drug development process would no doubt aid in selecting indication or a biomarker defined sub-indication increasing the change of a successful clinical trial.
One of the major challenges the research community is facing within oncology is modeling the interplay between immune cells and tumor cells. An example is the evaluation of combinations of tumor targeting antibodies and immune cell targeting antibodies. Cell line derived xenograft models fall short as due patient derived xenografts due to lack of a functional immune system in the mice. Syngeneic tumor models have a species barrier and requires that the antibodies bind to the orthologous targets in mice, which they often do not. A further limitation is the difference between mice and human immune systems, which is becoming increasingly apparent. More advanced humanized mouse models are not yet ready for prime time. A solution to this challenge is to develop 3D models of human tumor and autologous immune cells. Such models would be a great asset in the immune-oncology field and aid both in the discovery of new targets and in the development of existing drugs.

Symphogen therefore fully support this 3D model initiative and would be happy to collaborate with Bioneer in this area in the future.

Robert Burdorf (Sales Manager , I&L Biosystems Nordic A/S)
Tirsdag d. 8/5-18 kl. 18:10

The new approach using 3D Bioprinter for new biomaterials and cell containing applications for the future sounds very interesting for Bioneer A/S and opens new doors for new student generations.
Working with 3D Bioprinters over the last couples of years has proven to open up new possibilities for new applications in pharmaceutical drug testing, drug delivery systems, algae photosynthesis application, cosmetic application, tissue engineering, food application and many more.
I am looking forward to a fruitful future collaboration and let’s enable Bioneer A/S to explore the world of 3D Bioprinting as soon as possible.

Mads Aaboe Jensen (Group Leader, Roche Innovation Center Copenhagen)
Onsdag d. 9/5-18 kl. 16:47

This is indeed an important initiative - the ability to de-risk drug discovery projects using advanced 3D tissue models is something, I believe will be crucial going forward. The pharmaceutical industry is very much focused on being better at predicting early on what molecules will be successful in the drug discovery process. At a national level, 3D bioprinting is an area that we should start to build expertise within - the potential benefits are many. In my view, this may help and support both biotech start-ups and established pharmaceutical companies in Denmark.

Rikke Heidemann Olsen (lektor, KU)
Torsdag d. 17/5-18 kl. 08:47

The initiative is great, and definitely needed. While 2D cell cultures may have some value indeed, 3D cell cultures will be a giant step ahead for translational drug testing. I hope you will be successful in implementing the technology, and I see many opportunities for collaboration and tacking advantages of these facilities in my own research.

Erwin L Roggen (Ph.D., 3Rs Management and consulting ApS / ToxGenSolutions BV)
Tirsdag d. 22/5-18 kl. 11:21

The proposed activities address the needs that are currently advocated for by the scientific and regulatory societies. It is however important the apply these rather complex models to address questions that require them. These questions change throughout the process of product development. This is not sufficiently addressed in the current proposal, which is rather generic, also with respect to the parameters that will be measured.
There is however no doubt that 3D tissue/organ models, incorporating the cell types that are relevant for functionality, provide valuable information where 2D models do not. This information will help to understand the molecular and cellular mechanisms that drive efficacy and/or toxicity of a compound in the early preclinical phase. They may even show useful for optimisation of existing animal models currently used in the late preclinical phase.
Since the analytical tools are no specified I would urge to combine well established hypothesis driven tools with the open-minded data-driven tools (e.g. -omics) to maximally exploit the opportunities provided by 3D models.
It would strengthen the proposal is there was section dealing with in vitro pharmacokinetics/dynamics assessment.

Liselotte Brix (CSO, Immudex)
Tirsdag d. 22/5-18 kl. 11:38

Interesting and needed initiative. 3D modelling of immune cell migration in tumors are important for effective development of immunotherapeutic products. Liselotte Brix, CSO Immudex

Line Hagner Nielsen (Forsker, DTU Nanotech)
Mandag d. 28/5-18 kl. 20:36

Kompleksiteten af kroppen gør at det ikke er tilstrækkeligt at teste nye lægemiddelstoffer på simple cellemodeller, og det har vist sig at 3D cellemodeller øger korrelationen mellem in vitro og in vivo forsøg. Det er kompleks at sætte disse 3D cellemodeller op og kræver gode celledyrkningsfaciliteter samt kompetencer indenfor området og er derfor ikke altid nemt for mindre firmaer eller forskningsgrupper. Derfor er dette initiativ fra Bioneer meget lovende og vil kunne anvendes af mange både i industrien og fra academia.

Sven Frokjaer (Professor, Prodekan, Københavns Universitet)
Onsdag d. 30/5-18 kl. 10:57

Jeg finder det yderst relevant, at Bioneer deltager i udviklingen af 3D cellemodeller, idet disse systemer er vigtige eksperimentelle værktøjer i forbindelse med udvikling af nye lægemidler. Behovet er klart dokumenteret ved den betydelige interesse der er i life science litteraturen for netop 3 D cellemodeller både i relation til akademisk og industriel forskning og udvikling.

Frederik Diness (CEO, AAA Chemistry ApS)
Onsdag d. 30/5-18 kl. 16:33

3D cellemodeller er et oplagt redskab til både at effektivisere og reducere omkostningerne af lægemiddeludvikling. Især for mindre biotech-virksomheder vil adgangen til gode 3D vævsmodeller være en fordel, som alternativ til vævsforsøg in vivo der både er dyrere og mere komplekse at arbejde med. Indenfor kræftbehandling vil metoderne også være interessante som værktøj til karakterisering af de forskellige tumortyper, samt hvilke cytostatika der virker på dem. Denne type viden er særlig vigtig indenfor cancerområdet, da behandlingsregimerne typisk giver mange bivirkninger og det derfor er vigtigt, at der første gang vælges den bedste behandling til netop den givne type af cancerceller. Jeg kan derfor i høj grad støtte op om den beskrevne udvikling af 3D cellemodeller, samt tilhørende teknologi.

Flemming Madsen (Institutleder, Institut for Farmaci - Københavns Universitet)
Torsdag d. 31/5-18 kl. 11:16

Behovet er stort og det er et yderst relevant forslag, som Institut for Farmaci bakker fuldt op om. Fremtidens lægemiddeludvikling har brug for effektive, supplerende og alternative prædiktive metoder og teknikker. 3D vævmodeller/3D bioprinting er oplagte teknikker, og det er bare at bakke om udviklingen af dette. You ain't seen nothing yet.