HUB Organoid Technology

History

Previous attempts to grow epithelial stem cells in vitro resulted in very rare, genetically unstable cultures which have lost most molecular and clinical characteristics, as well as normal differentiation potential. In 2007, groundbreaking work by the Clevers` lab showed that, in adult intestinal tissue, Lrg5+ epithelial cells are the stem cells of the tissue (Barker et al., Nature 2007). Subsequent work by the Clevers` group led to the first `mini-organs` of the gut – organoids – a historical event that triggered a whole new era in in vitro patient like models and redefined the term organoid as we know it today.

Adult Stem Cells (ASCs) Advantages of HUB Organoids over Standard in vitro Models Patient-Derived Organoids (PDOs)

Adult Stem Cells (ASCs)

Aside from the discovery of Lrg5+ as an adult stem cell biomarker, the Clevers` lab also established
that – when provided with organ-specific growth factors and in the absence of a mesenchymal cellular niche – single adult stem cells (ASCs) can be used to generate self-organizing, intestinal epithelial structures.
The protocols established in using the technique allow for the expansion of ASC-derived organoids, from healthy and diseased (animal and human) cells. Importantly, no reprogramming or transformation is required resulting in a generally and epigenetically stable culture. HUB has further developed, optimized and standardized the protocols for implementing Organoid Technology within in vitro disease modelling, drug discovery and development, predictive diagnostics and personalized medicine. This efficient technology allows for generating organoids from any patient, with a very high success rate.

Advantages of HUB Organoids over Standard in vitro Models

– generated from ASCs – recapitulating organs` function, genetics and morphology of the organ they were derived from in vivo
– physiologically relevant modelling of healthy and diseased tissue biology
– rapid development and long-term expansion while maintaining genetic and phenotypic characteristics
– amenable to cryopreservation, gene editing, and all molecular, cell-biological and biochemical techniques used in cell line models
– suitable for engraftment or xenotransplant modelling
– unlike embryonic (ES) or pluripotent (iPS) stem cell derived organoids, HUB Organoids are derived directly from patients (tumor) and therefore are capable of capturing heterogeneity in diseases such as cancer
– unlike ES or iPS stem cell derived organoids, HUB Organoids are highly specialized for the tissue in which they reside, e.g. colon stem cells can only produce colon organoids

Patient-Derived Organoids (PDOs)

The breakthrough of the HUB Organoid Technology invention is the ability to establish a laboratory model of any epithelial disease from any patient, a `Patient in the Lab`.
Patient-Derived Organoids (PDOs) are excellent surrogates, capable of taking on the function of the tissue of origin and modelling a wide range of diseases in the areas of oncology, infectiology, genetics and metabolism. In addition to the development of multiple organoid models for human diseases, HUB has also generated large PDO biobanks of human tissue – including small intestine, colon, pancreas, lung, breast, and liver. These `living biobanks` not only capture the genetic diversity of healthy human populations, they also reflect the spectrum of individual variations that exist within a defined disease group.

The HUB Organoid Technology integrates this understanding of the epithelial tissues of most organs into a method that combines long-term in vitro expansion with the direct representation of clinical responses of individual human patients to their treatment.

Applications of HUB Organoids

As a drug discovery platform, HUB Organoids™ can be exploited for target discovery and genomic, functional, and safety studies at a scale that cannot be achieved by other patient-relevant models currently on the market.

– drug discovery and development: HUB Organoids allow generation of drug efficacy, safety, and mechanistical data.
– preclinical clinical trials: HUB Organoids provide preclinical translational information that can be used to identify patient populations before entering the clinical trials.
– companion diagnostics: HUB Organoids serve as ultimate biomarker identifying underlying mechanism and the clinical response of the treatment.
– living organoid biobanks: HUB Organoids capture disease relevance and heterogeneity of the patient population.
– predictive diagnostics: HUB Organoids represent individual patients and therefore enable designing targeted and personalized therapies as well as (pre)clinical patient stratification.

In addition, HUB Organoids are amendable to all normal experimental techniques used in the lab such as gene editing, cryopreservation and they can be easily manipulated. The organoid models are highly robust, produce consistent results and can therefore be applied in basic, translational, and clinical research. The capacity for long-term expansion allows for use in prolonged studies at significantly lower costs than primary cell systems of patient-derived samples.

Preclinical Clinical Living Organoid Biobank Predictive Diagnostics Safety/Toxicology

Preclinical

Drug discovery platform: HUB Organoids serve as an ideal platform for drug discovery screening, target discovery, and genomic and functional studies on a scale that could never be achieved for clinically relevant models.

Drug development: HUB Organoids provide drug efficacy, safety and mechanistic data. Furthermore, disease-specific collections of organoids enable preclinical stratification of patient populations.

Clinical

During clinical trials of new treatments carried out by the pharma industry, it is almost always unclear why an individual patient responds or doesn’t respond to the treatment. It is only when very specific biomarkers are known that we have an indication of why treatments are successful or not. HUB Organoids can serve as the ultimate biomarker because they can be generated from each patient in the trial. In vitro tests on these patient organoids will demonstrate if the lab response correlates to the clinical response, successful or not. The organoid therefore serves as a tool for identifying the mechanism underlying success and failure and/or serves as a companion diagnostic in the event that the treatment is successful.

Living Organoid Biobank

HUB has created a living organoid biobank from patient material that captures disease heterogeneity in diseases such as cancer, cystic fibrosis and Inflammatory Bowel Disease (IBD). The living organoid biobank is an expanding resource of highly characterised organoids for different organ systems and includes both the genetic and clinical data of the patient.

Predictive Diagnostics

The clinical application of HUB Organoids by generating organoids from individual patients provides a next generation tool for predictive diagnostics, designing targeted and personalised therapies as well as clinical patient stratification.

Safety/Toxicology

Organoids derived from mice, rats, dogs, and mini pigs allow for in vitro toxicology and research that will provide high throughput whilst maintaining in vivo relevance. In addition to providing a direct comparison between animal and human studies it will help decrease the use of animals in medical research.