Pain Management and Inflammation
Ingenium (www.ingenium-ag.com) is making a transition from being a genetics company to being a drug discovery and development company focused on pain management and inflammation. Since the start, the company has employed N-ethyl-N-nitrosourea (ENU) mutation to create mouse models for discovery and validation of novel targets.
The company developed a tool called Ingenotyping for its own internal target validation, as well as for big pharma and academic partners. Ingenotyping is based on Ingeniums archive that consists of ENU-mutated mouse DNA and frozen sperm samples, covering over 300,000 gene-specific mutations, with about ten different mutations in a single gene.
The archive is searched for mutations in a gene of interest. After bioinformatic analysis, sperm corresponding to mutations of interest can be used to create a mouse model via IVF. The method avoids complicated ES manipulation or chimera formation. Generation of homozygous animals takes around half the time needed to make a standard knockout, states Dr. Dembowsky.
A further advantage of Ingenotyping is that the range of mutations in each gene allows its function to be explored in more depth. We can often look at partial loss of function, whereas a knock-out may be lethal, which does not allow any validation.
The technology also has been applied to the rat, which may generate useful models for CNS disorders, although the Ingenium program on pain can readily be carried out in mouse models. Ingenium also has a long-term agreement with Elan (www. elan.com) on neuropathic pain management that uses both Ingenotyping and another tool called Deductive Genomics that uses ENU mutagenesis in a forward genetics approach for the discovery of novel targets.
Galpagos Genomics (www. galapagosgenomics.com) is a genomics-based drug discovery company with its own internal program in osteoporosis, osteoarthritis, Alzheimers disease, asthma, rheumatoid arthritis, and a service division, BioFocus (www. biofocus.com). The target discovery and validation technology used by the company involves introduction of human gene sequences by adenoviral vectors into primary human cells so that specific proteins are knocked-in or knocked-down. A genome-wide functional screen is followed by in vitro and in vivo validation assays designed to reveal which proteins are really relevant to a specific disease.
Modeling the disease through primary cell assays correlates better with human in vivo pathology than more traditional approaches. Relevant targets should be found more readily and, indeed, this approach has already led to the production of a number of small molecules for screening.
The company has partnerships with a range of firms, with BioFocus supplying libraries of adenoviral reagents targeting the whole human genome. SilenceSelect is the knock-down collection, while FlexSelect is a collection of human druggable full-length genes.
Finally, Interagon (www.interagon.com) is a spinout from Fast Search & Transfer (www.fastsearch.com) and has developed a Pattern Matching Chip that turns an ordinary PC into a tool for searching complex biological data. One of its applications is in the search for siRNAs that can be used in knock-down experiments.