Breaking News on Contract Research, Manufacturing & Clinical Trials

Library > Product Presentation

Target screening: Efficient identification and validation of disease-specific targets

Published: 12-Mar-2008 | Format: Web page | Document type: Product Presentation

 

 

 

 

 

Overview

 

As part of BioFocus’ full-suite of target-to-drug discovery services, we offer a technology platform that enables the efficient discovery of fully validated targets. We achieve this by applying our proprietary arrayed knock-in and knock-down libraries to over-express or silence human genes. These libraries focus on drugable as well as antibody targets. Human primary cell assays that model the disease of interest are used to analyze the gene libraries and select those proteins responsible for the disease.

 

Focusing on the drugable genome

 

We have built cDNA and shRNA collections of arrayed adenoviruses that either knock-in or knock-down human genes. In building these collections, we have focused on those targets deemed “drugable” by the pharmaceutical industry, i.e. small molecule tractable. This ensures that our partners focus their research efforts on those targets most likely 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.

 

Modeling diseases in human primary cells

 

Human primary cellular assays are the best systems to model human diseases in vitro. As compared to targets identified in animal or tumorgenic cell lines, those that are discovered and validated in human primary cells moreclosely mimic human invivophysiology. Adenoviral based systems have a distinct advantage over conventional transfection technologies in that these viruses efficiently introduce cDNA and shRNA constructs into a wide range of human primary cells. Adenoviral delivery also enables target identification and/or validation of the identified targets in patient material (for instance: synovial fibroblasts from rheumatoid arthritis patients). Cell types we have used in previous studies include:

 

– Primary mast cells

 

– Primary dendritic cells

 

– Primary endothelial cells

 

– Primary chondrocytes

 

– Primary osteoblasts

 

– Primary macrophages

 

– Primary keratinocytes

 

– Primary synovial fibroblasts

 

– Differentiated neuronal cells

 

More sophisticated assays

 

High-throughput screening:

 

Assays can be run in a high-throughput (96- or 384-well) format. To support these screening programs, we have built a set of bioinformatics tools as well as state-of-the-art multiplex and high content image analysis to evaluate the functional effects of modulated gene expression in a high-throughput manner.

 

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 approach allows the implementation of long-term assays such as cellular differentiation assays.

 

In vivo:

 

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

 

Broad range of disease areas

 

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 screening programs in:

 

– Allergic rhinitis

 

– Alzheimer's Disease

 

– Asthma

 

– Atherosclerosis

 

– Cancer

 

– Cystic Fibrosis

 

– Diabetes

 

– Huntington Disease

 

– Microbial/viral infections

 

– Obesity

 

– Osteoarthritis

 

– Osteoporosis

 

– Psoriasis

 

– Rheumatoid arthritis

 

Unique critical path approach

 

Our screening programs use a methodology that is fundamentally different from conventional genomics technologies. Together with the partner, 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” which regulate the disease phenotype. These hits are then passed through increasing complex validation assays, thereby increasing confidence in the biological relevance of the targets. Since we use primary human cells throughout the discovery process, we strongly believe this approach will increase the chances of translating an observed therapeutic effect into man.

 

Target discovery partnerships

 

All target discovery programs are set up according to our critical path approach, formed by a joint steering committee of BioFocus scientists and the partner. Before conducting the first screening experiment, we outline all steps of the screening and validation program, ensuring that all steps of the collaboration are carefully planned.

 

We are proud to be the target discovery partner of choice for a wide range of pharmaceutical, biotech, and patient organizations. We have long-standing, successful collaborations with companies such as GlaxoSmithKline, Wyeth, and Boehringer Ingelheim and have more recently entered into discovery partnerships with patient disease foundations including the High Q Foundation (in the area of Huntington Disease) and the Cystic Fibrosis Foundation.

 

 

 

 

 

 

Contact:

 

To learn more about our target screening platform and assay expertise, contact us at

 

info@glpg.com

 

 

Disease-relevant human primary cells

 

High-throughput functional assays

 

Assays of increased Target screening

 

Target Discovery

 

 

www.biofocus.com