We will be present at « High-Content and Phenotypic Screening » conference in Cambridge (25 – 26 April 2017) to talk about advantages of 3D culture in phenotypic screening, during the user meeting of Molecular Devices.

Cellular assays in 3D culture have shown many advantages to better mimic the in vivo situation. A few examples in oncology, CNS and metabolic diseases, will be presented during this talk. High-Content Screening (HCS) devices, such as the ImageXpress Micro confocal from Molecular Devices, are now fast enough and sensitive enough to allow image acquisition in 3D cellular models. Nevertheless, to go further, perceptions and processes need to be changed. We will discuss cutting-edge new technologies, including virtual and augmented realities, deep learning and machine learning, and explain how these new technologies can be of benefit to phenotypic screening.

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Idiosyncratic drug-induced liver injury (DILI) is a rare adverse drug reaction resulting in liver injury, and a cause of failure in both clinical and post-approval stages of drug development. Predictive the toxicity of new chemicals entities (NCE) is a key challenge to the pharmaceutical industry (FDA, 2009). In order to avoid the use of laboratory animals, and to reduce the cost of pre clinical studies, in vitro toxicology combined the use of cellular models with the measurements of several cell health endpoints in order to predict the hepatotoxicity of NCE. Primary Human Hepatocytes and heptocyte-like cell lines such as HepaRG, Upcytes and HepG2 are commonly used in NCE safety assessment. However, standard cellular assays have shown their limitation to specifically predict DILI potential of NCE (Sison-Young et al., 2017). The era of high content analysis, and especially phenotypic screening, bring new strategy for toxicologist to predict DILIs and their underlying mechanisms, and provides an effective means to reduce drug development failures due to insufficient safety (Xu, 2015).

HCS Pharma is daily developing new cellular assay based on phenotype characterization for toxicology. See our website for more information and feel free to contact us !

Bibliography

In this article, they employed microglia-based phenotypic screenings to search for small molecules that modulate the release of detrimental proinflammatory cytokines and they identified a novel pharmacological inhibitor of neuroinflammation (named GIBH-130) which was validated to alter phenotypes of neuroinflammation in AD brains.

“Currently, anti-Alzheimer’s Disease (AD) drug discovery using target-based approaches is extremely challenging due to unclear etiology of AD and absence of validated therapeutic protein targets. Neuronal death, regardless of causes, plays a key role in AD progression, and it is directly linked to neuroinflammation. Meanwhile, phenotypic screening is making a resurgence in drug discovery process as an alternative to target-focused approaches.”

Source : http://pubs.acs.org/doi/abs/10.1021/acschemneuro.6b00125

After having been eclipsed by Target-Based Screening, Phenotypic Screening is finally shining again

The Right Combination

“We take the idea of using drug combinations to treat a disease and apply it to the phenotypic screen. In our particular case, we have successfully employed this approach to multidrug-resistant bacteria and the Ebola virus,” expounds Wei Zheng, Ph.D., a group leader at the National Center for Advancing Translational Sciences, part of the National Institutes of Health (NIH).

Thinking Inside the Black Box

“Remember the ‘Rule of 3’ for phenotypic screens,” urges Dr. Hett. This rule refers to the right cells, the right stimulus, and the right readout. The better the disease is understood, Dr. Hett adds, the better the model system that can be constructed.

Source : http://www.genengnews.com/gen-articles/the-reemergence-of-phenotypic-screening/5675/

Using iPS, researchers are moving very quickly in understanding cell differentiation and already manage to recreate a mini-organ in vitro after 20-30 days of differentiation. These mini-organs of brain, liver, heart and so one can be used as in vitro assay to test efficiency of new drugs. Furthermore, new perspectives in personalized medicine also open in oncology, stem cells from cancerous tissue of the patient can be grown to produce a tumor organoid. From the patient cells to find new drug using phenotypic screening is now a new opportunity to innovate in medicine.

Source (in french) : http://www.sciencesetavenir.fr/sante/20160212.OBS4547/la-fabrique-de-micro-organes-humains.html

To incresase the relevance of the early stage of drug research process, using patient derived-cells is really the good way. This can be now feasible by using iPSCs. This is nicely described in the recent article published on GEN website.

“The ability to make induced pluripotent stem cells (iPSCs) from adult human somatic cells and use those iPSCs to produce any cell type in the human body opens new avenues for drug discovery. Human iPSCs can enable phenotypic screening efforts by supplying unlimited amounts of relevant cell types derived from diverse genetic backgrounds.

Newly available biobanks of high-quality iPSCs from hundreds of donors, representing a growing number of disease states, are making it easier to create robust phenotypic screening programs. By 2018, publicly available biobanked iPSC lines are expected to number in the thousands (Novak, 2015).”

To read the full article published on GEN, follow this link : http://www.genengnews.com/gen-articles/enabling-phenotypic-screening/5657/

High Content Screening can be used in several approach: HCS of small molecules library to find compound whch has potential positive effect on disease, HCS of siRNA to find new target in a disease… Here, the author has reported te use of phenotypic screening to find coumpound which has neuronal differenciation effect of stem cells.

Curated from A chemically defined substrate for the expansion and neuronal differentiation of human pluripotent stem cell-derived neural progenitor cells

By phenotypic screening, these authors have identified small molecules, that protected podocytes against injury in vitro. This  findings identify pyrintegrin as a potential therapeutic candidate and show the use of podocyte-based screening assays for identifying novel therapeutics for proteinuric kidney diseases.

To know more of this article, follow this link : http://www.ncbi.nlm.nih.gov/pubmed/25858967

More and more articles show the advantages of culture compared to 2D in field. This article describe how to do high throughput using 3D culture by rapid size profiling analysis over time on tumor spheroids.

“Tumor size is the most frequently used in vivo endpoint when assessing antitumor efficacy in animal xenograft models, whereas proliferation is the more typically evaluated growth endpoint in vitro using two-dimensional (2D) monolayer cultures. Such 2D in vitro assays frequently fail to correlate with in vivo observations, owing to the inability of 2D cultures to recapitulate the native tumor microenvironment described above. Three-dimensional (3D) tumor microtissues, or multicellular tumor spheroids, are considered a more representative, organotypic model for assessment of tumor growth. They contain layers of cells that exhibit more in vivo-like size- and gradient-dependent proliferation and viability profiles.”

To know more about this article, follow this link: http://www.genengnews.com/gen-articles/phenotypic-drug-discovery-in-3d/5303/

In this presentation, Dr. Kamyar Hadian (head of the and Screening Platform’ at the HelmholtzZentrum München in Munich/Germany) talk about use in – and microtissue-based assays.

has highly emerged in the past years. Especially High-Content Screening (HCS) has gained strong acceptance in the field of target validation and compounds screening as a method to follow more innovative and sophisticated assays …

I was really impressed by the size and quality of the Drug Discovery 2014 organised by ELRIG in Manchester. More than 1,500 scientists participated in this meeting and nearly 100 exhibitors were present. Phentoypic screening and high content screening were prominent in this conference and we could hear researchers from Roche, Astrazeneca, Merck Serono or Cancer research UK / UK-NPSC (National Screening Phentypic center) to explain us how they have implemented phenotypic screening and HCA / HCS in their lab and process of drug discovery.
Here, you can hear an interesting interview from Dr. Peter Simpson, Co-Organizer of Elrig Drug Discovery 2014, directed by SelectScience :

Dr. Peter Simpson Discusses ELRIG Drug Discovery 2014

Dr. Peter Simpson Discusses ELRIG Drug Discovery 2014

The Scottish Government believes in the new strategy of phenotypic screening rather than target screening since they invest £8 million for university of Dundee and as they said: “Phenotypic screening is thought to be a powerful method for drug discovery because it offers the opportunity to go beyond the focus on single drug targets, 
which has traditionally been the most widely adopted approach for drug discovery.

Current systems have been plagued by low success rates in early development, as well as expensive late-stage failure of many new drugs in second or third phase trials, insiders said.”

source: http://www.thecourier.co.uk/news/education/dundee-university-to-be-home-to-new-drug-screening-centre-after-8-million-investment-1.344047

“While classical screens with a single readout only allow you to quantify the measured effect, high-content screens promise more: Additional phenotypic changes can be observed and also quantified, allowing in principle a distinction of the chemical responses into three classes: similar to untreated cells; similar to control-treated cells; or dissimilar to both.”

To read more on this article, follow the link bellow!

Source: http://www.genengnews.com/insight-and-intelligence/the-renaissance-of-phenotypic-research/77900057/

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