Adenoviral technology and applications

Technology platform

We employ the unique properties of adenoviruses to study gene function in human cells. These 'shuttle vehicles' can deliver cDNA or shRNA into a broad range of human primary cells. Our full length-cDNA (FLeXSelect) and shRNA (SilenceSelect) collections of arrayed adenoviruses are very effective to knock-in or knock-down human genes in primary cells. The libraries focus on targets deemed druggable by the pharmaceutical industry, i.e. small molecule tractable. This greatly increases the chance to yield clinically beneficial compounds. In addition, we have expanded the knock-down library with antibody targets to enable the identification of targets for antibody drugs.

In addition to our off-the-shelf cDNA and shRNA collections, we can generate viruses expressing constructs to either over-express or knock-down your genes of interest. We also offer custom purification of our adenoviruses. The high standards of our purified reagents allows for the progression of projects to in vivo animal studies.

Through the resulting over-expression or silencing of genes, complex functional studies on the resulting protein's role in a specific biological pathway or disease pathway can be performed. Our discovery platform offers several advantages over conventional approaches:

• Efficient delivery to a wide range of human primary cells
• Stable, transient and long-term expression
• Arrayed format for high-throughput readout

Modeling diseases in human primary cells

We are at the forefront of using human primary cellular assays to model human diseases. By combining our disease-biology expertise with our technology platform, we can accelerate target discovery in any disease area. This expertise is reflected by our successful target discovery programs in:

• Inflammatory diseases
• Bone and joint diseases
• Respiratory diseases
• Neurodegenerative diseases
• Obesity and diabetes

Human primary cellular assays are the best systems to model human diseases in vitro. Human primary cells closely mimic human in vivo physiology in contrast to animal or tumorgenic cell lines. Our adenoviral system has some distinct advantages over conventional transfection technologies.

We have developed 17 medium- and high-throughput customized human primary cell assays for screening in different disease areas with an average of 15,000 data points per screen. The below list illustrates the types of cells we have successfully screened. We can also work with you to develop new assays relevant to your specific disease area.

The platform has a track record across a broad range of human primary cell types.

• (Pre) adipocytes
• Beta cells
• Bronchial epithelial cells
• Chondrocytes
• Dendritic cells
• Endothelial cells
• Fibroblasts
• Hepatocytes
• Keratinocytes
• Macrophages
• Mast cells
• Osteoblasts
• Skeletal myoblasts and myotubes
• Synoviocytes
• Mesenchymal stem cells
• Embryonic stem cells
• Astrocytes derived from stem cells
• Cardiomyocytes derived from stem cells
• Motor neurons derived from stem cells
• Striatal neurons derived from stem cells
• Human cell lines (>30)

Unique critical path approach

Our methodology is fundamentally different from conventional genomics technologies. We apply a 'critical path' approach to deliver validated drug targets into compound screening. For each disease program, our libraries are functionally screened in human primary cell disease models to identify hits that regulate the disease phenotype. These hits are then passed through increasing complex validation assays, establishing the biological relevance of the targets. The primary human cell as the basis for the target discovery process increases the chances of translating an observed therapeutic effect into man.

As our understanding of the complex interplay of networks and pathways within cellular processes increases, the need for ways to screen compounds in the correct disease context also grows. Disease-relevant assays in human primary cells that are amenable to high-throughput screening allow you to accelerate drug discovery by finding the right lead candidate quickly.

Target discovery collaborations

We apply our expertise in developing disease models in human primary cells to identify novel, disease modifying targets. These targets then serve as a basis for effective drug discovery programs. Based on this unique technology platform, which combines our adenoviral collections with human cellular assays and state-of-the-art drug discovery expertise, we have become one of the world's leading providers of target-to-drug discovery partnerships.

High-throughput screening: Assays can be run in a high-throughput (96- or 384-well) format, supported by our bioinformatics tools and multiplex and high content image analysis.

Long-term studies: In contrast with synthetic siRNA, adenoviral-mediated transfer of shRNA induces long term (> 10 days) knock-down, allowing efficient silencing of the gene of interest. Furthermore, this feature allows the implementation of complex biological assays such as cellular differentiation assays.

Adenoviral technology can also be applied to validate targets in vivo: constructs identified as hits in target discovery can be used directly in animal models to demonstrate the effect on the disease.