In Belgium, there is a political will to restrain health expenses linked to drug prescription: authorities aim to develop means to reduce useless prescription and to improve current treatments. In the standard medical practice, pharmacogenetic tests would allow to individualize treatments in order to prescribe more efficient and safer treatments, adapting doses to each patient. Instead of relying on lengthy trial-and-error approaches for optimizing drug therapy, physicians may achieve earlier success using their patient’s metabolic profile as a guide to dosing.
There is an extensive scientific research showing that inherited genetic variations in the CYP2D6 and CYP2C19 genes can play an important role in how patients metabolize, and therefore respond to, many widely prescribed drugs. The enzyme encoded by the CYP2D6 gene plays a primary role in the metabolism of drugs used to treat severe depression, schizophrenia, bi-polar disorder, cardiovascular disease treated with beta-blockers, attention deficit/hyperactivity disorder (ADHD), and others. The enzyme encoded by the CYP2C19 gene metabolizes many anti-convulsants, proton pump inhibitors, benzodiazepines, and anti-malarials. Both the CYP2D6 and CYP2C19 enzymes are involved in the metabolism of certain tricyclic antidepressant drugs use to treat depression.
Recently, Roche Diagnostics, developed the Amplichip CYP450 test. This test is the world’s first pharmacogenetic microarray-based test approved for clinical use (Cleared for in vitro diagnostic use in the US and EU). The AmpliChip CYP450 Test provides comprehensive coverage of gene variations for the CYP2D6 and CYP2C19 genes, which play a major role in the metabolism of an estimated 25% of all prescripted drugs. The test distinguishes 29 known polymorphisms in the gene CYP2D6, including gene deletion and duplication (with the ability to discern which variation of the gene has been duplicated). Detection of these polymorphism results in the identification of 33 unique alleles. It also detects two major polymorphisms in the CYP2C19 gene.
Patients treated with drugs that are extensively metabolized by CYP2D6 and CYP2C19 enzymes are at increased risk for experiencing toxicity with standard dosing if they are poor metabolizers, while ultra-rapid metabolizers may not achieve therapeutic levels of the same drug in their blood with standard dosing. In the case of pro-drugs (drugs that require metabolic enzyme activity before they become the active therapeutic compound in the body), the opposite phenomenon occurs and poor metabolizers will obtain no benefit for these drugs.
DNAVision is conducting, with the support of the Walloon region, a research project focusing on the amplichip technology.
The Amplichip research project aims to demonstrate the pharmaco-economic interest of pharmacogenetic through the retrospective study of patients treated with 5 drugs known to have a narrow therapeutic window and to represent a major cost for the social security:
DNA from patients with well documented clinical history are collected and analyzed using the Roche Amplichip technology. The association between genotype of the CYP2D6 and CYP2C19 enzymes and drug response phenotype is analyzed using statistical tools and then, pharmaco-economic analysis will be performed to demonstrate that there is an economic interest to genotype patient prior to drug prescription.
The samples are collected in different medical centers across Belgium with the help of area specialists.
With the financial support of the Région Wallonne, DNAVision is going to develop an ambitious research programme in the area of personalised medicine. This will entail developing a therapeutic identity card or THERAPID. This card will be a high throughput DNA chip, making it possible to predict the toxicity or non-response to a medicinal product already on the market. The originality of this card lies in the fact that it will take into account, firstly, toxic side effects linked to the metabolism of medicinal products and, secondly, the integrity of the target of the medicine (e.g. receptor). This tool will integrate all known genetic mutations with a potential pharmacological effect. In addition, this research should lead to the discovery of new mutations in the targets of usual medicines.
Grants from Belgium Walloon Region to support biomarkers research and validation in collaboration with GlaxoSmithKline, IBA, Eurogentec and Eppendorf Array Technologies.
The KeyMarker project is within the life sciences cluster and it focuses on the pathographies of cancer, inflammatory disease and disease of the brain. The aim of the KeyMarker project is to identify new types of molecules, genes or proteins whose presence is closely linked to the disease and its evolution. The presence of these key markers will be highlighted and monitored by the most recent techniques in medical imaging, as for example in PetScan. KeyMarker has a working budget of 7.2m€. 6m€ of which comes from the Walloon government and the rest is capital contributed by the partners.
Goal: The objective of the EXERA project is to develop novel 3D in vitro models of mouse tissues from five major organs for the pharmaco-toxicological analysis of Estrogen Receptors-Interacting Compounds (ER-ICs): liver, skin and bone (non reproductive systems), ovary and testis (male and female reproductive systems).
Work content: This objective will be pursued through a Work Programme which allies an integrated scientific approach between innovative technologies such as the 3D-culture device, known as “Rotary Cell Culture System” (RCCS Technology adapted to the needs of this project), established transgenic mouse lines (estrogen-reporter mice, here called MOUSE-1) and genomic platforms for ER-ICs characterization. Our strategy is planned around 5 main points including, besides the mentioned technologies, multiple cell cultures quality controls, immortalisation control, cell banking and the use of specific markers of estrogenic action and cell differentiation/health, in order to obtain estrogen-responsive 3D-cultures of well differentiated mouse cells.
Expected Results and Related Benefits: The corresponding work programme will be ensured by an important involvement of the whole partnership and by a high degree of coordination between 7 private and 3 public institutions. The expected results of our effort will be scientifically, socially and economically relevant: 1) application/adaptation of new 3D-culture technologies to cell cultures devoted to the study of ER-ICs; 2) constitution of a cell bank and, finally 3) a battery of differentiated 3D cell-based systems derived from estrogen-reporter mice for basic and applied research (e.g. pharmacology and toxicology), public use and industrial use.
MXA assay to predict Interferon resistance in multiple sclerosis.