Unveiling new genetic insights in rheumatoid arthritis for drug discovery through Taxonomy3 analysis.

Genetic support for a drug target has been shown to increase the probability of success in drug development, with the potential to reduce attrition in the pharmaceutical industry alongside discovering novel therapeutic targets. It is therefore important to maximise the detection of genetic associations that affect disease susceptibility. Conventional statistical methods such as genome-wide association studies (GWAS) only identify some of the genetic contribution to disease, so novel analytical approaches are required to extract additional insights. C4X Discovery has developed Taxonomy3, a unique method for analysing genetic datasets based on mathematics that is novel in drug discovery. When applied to a previously published rheumatoid arthritis GWAS dataset, Taxonomy3 identified many additional novel genetic signals associated with this autoimmune disease. Follow-up studies using tool compounds support the utility of the method in identifying novel biology and tractable drug targets with genetic support for further investigation.

Company profile: PGXIS Ltd.

Pharmacogenomic Innovative Solutions Ltd (PGXIS) was established in 2007 by a group of pharmacogenomic (PGx) experts to make their expertise available to biotechnology and pharmaceutical companies. PGXIS has subsequently established a network of experts to broaden its access to relevant PGx knowledge and technologies. In addition, it has developed a novel multivariate analysis method called Taxonomy3 which is both a data integration tool and a targeting tool. Together with siRNA methodology from CytoPathfinder Inc., PGXIS now has an extensive range of diverse PGx methodologies focused on enhancing drug development.

FK962 and donepezil act synergistically to improve cognition in rats: potential as an add-on therapy for Alzheimer's disease.

FK962 is a member of a novel class of compounds that promote somatostatin production in the brain, and is being developed as a treatment for patients with Alzheimer's disease. As acetylcholinesterase inhibitors such as Aricept© (donepezil) are widely used to treat these patients, it is important to confirm that potential new medicines in this disease area can be co-administered with drugs such as Aricept. To study the effect of FK962 in combination with donepezil, touchscreen methodology was used to measure the effect on cognition in rats. Doses of FK962 and donepezil were identified that resulted in minimal cognition enhancement when given separately. There was strong evidence (p=0.002) of a treatment difference between the combination of FK962/donepezil and FK962 alone: the estimated treatment difference is 5.47 (95% CI: 2.19-8.75). There was also evidence (p=0.017) of a treatment difference between the combination of FK962/donepezil and donepezil alone: the estimated treatment difference is 4.01 (95% CI: 0.77-7.26). Therefore, a combination of low doses of FK962 and donepezil showed a significantly greater effect on cognition than low doses of either compound alone. This is the first time that FK962 has shown activity in a reward-based model of cognition. In addition, these data suggest that this compound could beneficially be given in addition to Aricept to treat Alzheimer's disease patients.

Pharmacogenomic Innovative Solutions.

Pharmacogenomic Innovative Solutions is a new company of pharmacogenomics experts. It uses its expertise in pharmacogenomics to enhance the efficiency of drug development, to make more drugs available for patients, and to increase the clinical effectiveness of drugs, in order to ensure patients receive better treatment. To do this, the company has two parts to its business strategy: consultancy to pharmaceutical and biotechnology clients to optimize development pipelines for drug launch; and partnering with drug-discovery organizations to increase its portfolio through in-licensing or codevelopment.

Genetic variants in the epithelial sodium channel associate with oedema in type 2 diabetic patients receiving the peroxisome proliferator-activated receptor gamma agonist farglitazar.

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are highly effective in the treatment of type 2 diabetes. In some patients, PPARgamma ligands are associated with fluid retention/oedema, for which the mechanism is not fully understood. A pharmacogenetic study was undertaken to investigate effects of variations in 21 candidate genes related to epithelial sodium channel (ENaC) pathways on oedema. This study used DNA samples collected from type 2 diabetes phase III clinical trials of the PPARgamma agonist farglitazar (administered alone or in combination with insulin or glyburide) and investigated oedema reported as an adverse event as phenotype. Initial case-control analysis of oedema identified candidate gene single nucleotide polymorphisms with significant associations. These included three polymorphisms in ENaCbeta subunit (SCNN1B) that showed significant associations (P<0.05) with the two combination treatments in discrete regions of the gene, but not farglitazar treatment alone. Sequencing of SCNN1B in 207 Caucasian participants receiving farglitazar plus insulin or glyburide combination therapies, identified additional polymorphisms that were also significantly associated with oedema (P<0.0005) and maintained the treatment-regional associations. Further covariate analysis accounting for clinical factors influencing oedema supported these observations. One of the SCNN1B polymorphisms, at position -405 of the 5' flanking region (rs34241435), was predicted to modify transcriptional interactions and in a transfected COS cell luciferase reporter gene assay exhibited higher promoter activity. These exploratory studies provide clinical pharmacogenetic and functional genomic evidence to support a pivotal role for ENaC regulation in PPARgamma-induced oedema and provide insight into mechanisms and possible management of this side effect.

Pharmacogenetics in drug development.

Over the last two decades, identification of polymorphisms that influence human diseases has begun to have an impact on the provision of medical care. The promise of genetics lies in its ability to provide insights into an individual's susceptibility to disease, the likely nature of the disease and the most appropriate therapy. For much of its history, pharmacogenetics (PGx-the use of genetic information to impact drug choice) has been limited to comparatively simple phenotypes such as plasma drug levels. Progress in genetics technologies has broadened the scope of PGx efficacy and safety studies that can be implemented, impacting on a broad spectrum of drug discovery and development activities. Recent PGx data show the ability of this approach to generate information that can be applied to dose selection, efficacy determination and safety issues. This in turn will lead to significant opportunities to affect both the approach to clinical development and the probability of success--the latter being an important aspect for pharmaceutical companies and for the patients who will benefit from these new medicines.

Purification of glutamate dehydrogenase from liver and brain.

Two alternative procedures are described for the purification of the major form of glutamate dehydrogenase (L-glutamate-NAD(P)+ oxidoreductase (deaminating), EC 1.4.1.3: GDH) from ox liver and brain. The first involves affinity chromatography on a column of the allosteric inhibitor GTP bound to Sepharose, whereas the other uses a bifunctional ligand (bis-NAD+) composed of two NAD+ molecules linked together by a spacer arm to precipitate the enzyme in the presence of the substrate analogue glutarate. In both procedures the affinity steps are preceded by ammonium sulfate precipitation and ion exchange chromatography on DEAE cellulose. Procedures for the synthesis of GTP-Sepharose and bis-NAD+ are described and the ancillary procedures, including the assay of GDH activity and the determination of protein concentration, are also presented.