Drug Target Pathways Research Articles

Theranostics Health: personalized therapy and diagnosis today.

Theranostics Health is a young company using mature proprietary technology to make personalized medicine possible today. The firm provides pharmaceutical scientists, clinical trial clinicians and treating physicians with highly detailed portraits of protein drug target pathways and critical patient data about drug activity, selectivity and specificity. Its assays and therapeutic tools provide unprecedented cancer treatment and drug response information and show strong prospects for application to a wide range of disease indications. Theranostics' leadership believes that its products and services will have major impact on individualized therapeutic efficacy and treatment toxicity, while reducing treatment and drug-development costs and expediting the introduction of new pharmaceutical solutions.

Potential Genetic Causes of Heterogeneity of Treatment Effects

Nongenetic biologic and lifestyle-related factors, including age, sex, hepatic/renal function, diet/exercise practices, illness severity, smoking, and alcohol consumption habits can account for the heterogeneity of treatment effects (HTE). However, even when these factors are taken into account, considerable variation remains unexplained and could potentially be attributable to genetic differences between patients. Drug response may be dictated by variation in genes involved in both pharmacokinetic (PK) (absorption, distribution, metabolism, excretion [ADME]) and pharmacodynamic (PD) (receptors, ion channels, enzymes, immune system) pathways. Functional variants of the ADME genes can result in patients being poor, intermediate, efficient, or ultrarapid metabolizers of specific agents, thereby affecting efficacy and/or susceptibility to adverse drug reaction and necessitating individualized dosing. A well-documented example of ADME gene variation is the debrisoquine polymorphism, which is characterized by markedly different metabolism of numerous commonly prescribed drugs based on variants of the cytochrome P450 2D6 gene. Variants of genes regulating PD pathways cause altering of drug target pathways, which may affect efficacy in a more pronounced manner. Examples of gene variants affecting PD pathways include those coding for dopamine metabolism, synthesis, and transport. These gene variants may act independently, in combination with each other, and/or in combination with PK genes to affect drug response, for example to antipsychotic medications. Increased understanding of a patient’s genotype and its corresponding effect on drug response would be useful to the practicing clinician in choosing an effective drug and in optimizing the dose in a timely manner.

Aquaporin-7 and glycerol permeability as novel obesity drug-target pathways

Advances in determining the mechanisms that underlie the control of energy balance in mammals have recently been provided by the discovery and characterization of aquaporin-7 (AQP7), a water-glycerol transporter that is present in the plasma membrane of fat-storing cells (adipocytes). Recent studies have shown that the absence of AQP7 expression in fat cells increases glycerol kinase activity, boosting triacylglycerol synthesis and ultimately leading to obesity. Thus, AQP7 operates as a glycerol channel in vivo, whereby adipocyte glycerol permeability has a key role in the regulation of fat accumulation.

A novel RNAi library based on partially randomized consensus sequences of nuclear receptors: Identifying the receptors involved in amyloid β degradation

Combinatorial gene inactivation using an RNAi library is a powerful approach to discovering novel functional genes. However, generation of a comprehensive RNAi library remains technically challenging. In this report, we describe a simple and novel approach to designing gene-family-specific RNAi libraries by targeting conserved motifs using degenerate oligonucleotides. We created an siRNA library in the pHUMU vector using partially randomized sequences targeting the consensus region in the ZnF_C4 signature motif of the nuclear hormone receptors and thus against the entire receptor superfamily. For proof of principle, we adapted a reporter assay to screen this library for receptors that might be involved in reducing amyloid β peptide accumulation. We modified a previously described luciferase reporter assay to measure the amyloid β precursor cleavages occurring only between β- and γ-secretase cleavage sites, thus excluding the major γ-secretase activities that could generate neurotoxic Aβ peptides. Our screen using this assay identified siRNA vectors that specifically increase the Aβ40/42 cleavage and pointed to a potential receptor target, ROR-γ. SiRNAs targeting other regions of ROR-γ not only confirmed the observed reporter activity but also reduced the level of the toxic Aβ peptides. The results demonstrated a general principle for the creation and application of this RNAi library approach for functional gene discovery within a predefined protein family. The discovered negative effect of ROR-γ on the degradation of the toxic Aβ peptides may also provide a potential drug target or targetable pathway for intervention of Alzheimer disease.

Clock genes: influencing and being influenced by psychoactive drugs

Although clock genes are the hallmark of circadian rhythms, they are also currently considered as transcription factors that have a prominent role in the pharmacology of the CNS. The expression of these transcription factors in the mammalian brain is not only intrinsically rhythmic but is also modulated by external inputs and hormones. An altered expression of clock genes, as evidenced in transgenic mice, has a profound influence on the behavioral effects of psychoactive drugs. Focusing on clock genes expressed in the brain might lead to the discovery of novel drug-target pathways.

Pharmacogenetics and obesity: common gene variants influence weight loss response of the norepinephrine/dopamine transporter inhibitor GW320659 in obese subjects

GW320659, a highly selective neuronal norepinephrine and dopamine re-uptake inhibitor, has been evaluated for the treatment of obesity. Scrutiny of the weight loss data from a phase II study (GlaxoSmithKline study OBS20001) showed a wide variation in weight loss response following GW320659 treatment and the possibility that the study population might include subgroups with enhanced weight loss response. Pharmacogenetic analysis was performed in 191 subjects prospectively ascertained from a Phase II dose ranging study to evaluate the influence of genotype on weight loss efficacy and safety of GW320659 in obese subjects. Common genetic polymorphisms in the drug target (norepinephrine transporter protein 1, SLC6A2) and mechanism pathway (NMDA receptor channel NR1 subunit, GRIN1) were associated with increased weight loss following GW320659 treatment in a proportion (36%) of the study population. In the patient subgroup selected for these genotypes, GW320659 (15 mg/day) produced a significant difference in mean weight loss of 7.84 kg (SD 5.23, n = 14), compared to 2.53 kg (SD 5.17, n = 24) in the subgroup that did not possess the genotypes (P = 0.006). This subgroup also showed a highly significant weight loss response for GW320659 compared to placebo (+0.31 kg, SD 3.32, n = 16) with the same genotypes (P < 0.0001). In addition, there was no difference in placebo response between either subgroup. Polymorphisms in SLC6A2 and GRIN1 could be used to maximize effective obesity pharmacotherapy by norepinephrine/dopamine transporter inhibitors by identifying patients that may be predisposed to particularly good treatment weight loss response.

The connections between C75 and obesity drug-target pathways

Obesity and its attendant disorders, such as Type II diabetes, have reached epidemic proportions in the USA, and their prevalence is increasing globally. C75 is a small-molecule inhibitor of fatty acid synthase (FAS) and a stimulator of carnitine palmitoyl 1 activity, which causes profound weight loss in mice. Although C75 is not a compound that is destined for human drug development, it has provided two potential pathways to target in obesity therapy: fatty acid synthesis and fatty acid oxidation. In this article, we discuss the latest data challenging the relationship between fatty acid synthase inhibition and C75-induced anorexia.

Microarray technology: a review of new strategies to discover candidate vulnerability genes in psychiatric disorders.

An international effort is in progress to discover candidate genes and pathways associated with psychiatric disorders, including two of the most serious diseases, schizophrenia and mood disorders, through the use of new technology-microarrays. Instead of studying one gene at a time, microarrays provide the opportunity to analyze thousands of genes at once. This article reviews the steps in this discovery process, including the acquisition and characterization of high-quality postmortem brain tissue, RNA extraction, and preparation and use of microarray technology. Two alternative microarray methods and factors affecting the quality of array data are reviewed. New analytical strategies are being developed to process the massive data sets generated by microarray studies and to define the significance of implicated genes. Array results must be validated by other methods, including in situ hybridization and real-time polymerase chain reaction. Identified genes can also be evaluated in terms of their chromosomal locations and possible overlap with regions of suggestive linkage or association identified with genome-wide linkage analysis in psychiatry and in terms of overlap with genes identified by microarray studies in animals administered psychoactive drugs. Microarray studies are only the first major step in the process. Further efforts in the investigation involve multiple strategies for studying function and gene structure, including transgenic and knockout animal studies. Microarrays present a methodology that can identify genes or pathways for new and unique potential drug targets, determine premorbid diagnosis, predict drug responsiveness for individual patients, and, eventually, initiate gene therapy and prevention strategies.

Pharmacogenomics and schizophrenia

Although antipsychotic drugs are effective in alleviating schizophrenic symptoms, individual differences in patient response suggest that genetic components play a major role, and pharmacogenetic studies have indicated the possibility for a more individually based pharmacotherapy. The new field of pharmacogenomics, which focuses on genetic determinants of drug response at the level of the entire human genome, is important for development and prescription of safer and more effective individually tailored drugs. DNA microarray (DNA chip) analysis enables genome-wide scanning, using the high-density single nucleotide polymorphisms map. Pharmacogenomics will aid in understanding how genetics influence disease development and drug response, and contribute to discovery of new treatments. The rate of discovery of those polymorphisms will depend on the quality of the drug response phenotype. Prospective genotyping of schizophrenic patients for the many genes at the level of the drug target, drug metabolism, and disease pathways will contribute to individualized therapy matching the patient's unique genetic make-up with an optimally effective drug.

Impact of genomics on drug discovery and clinical medicine

Genomics, particularly high-throughput sequencing and characterization of expressed human genes, has created new opportunities for drug discovery. Knowledge of all the human genes and their functions may allow effective preventive measures, and change drug research strategy and drug discovery development processes. Pharmacogenomics is the application of genomic technologies such as gene sequencing, statistical genetics, and gene expression analysis to drugs in clinical development and on the market. It applies the large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism, or disease pathways. The potential implication of genomics and pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to genetic and specific individual markers, selecting medications and dosages that are optimized for individual patients. The possibility of defining patient populations genetically may improve outcomes by predicting individual responses to drugs, and could improve safety and efficacy in therapeutic areas such as neuropsychiatry, cardiovascular medicine, endocrinology (diabetes and obesity) and oncology. Ethical questions need to be addressed and guidelines established for the use of genomics in clinical research and clinical medicine. Significant achievements are possible with an interdisciplinary approach that includes genetic, technological and therapeutic measures.

The developing role of pharmacogenetics in psychiatry.

A great interindividual variability exists in biological response to drugs. This variability is partly attributable to pharmacodynamic factors (drug - receptor interactions) and partly to pharmacokinetic factors. Drugs can be eliminated from the body by renal clearance, metabolism or both. Although every tissue has some ability to metabolise xenobiotics like drugs, the liver is the principal organ of biotransformation. Major metabolising enzymes are the cytochrome-P450 mono-oxygenases, epoxide hydrolase, glucuronosyl-transferase, acetyl-transferase, sulfo-transferase and xanthine oxidase. Some of these enzymes display in a subset of subjects a 'normal' activity and in another subset of subjects a reduced or a greatly increased activity. This altered activity may be genetically determined and is then called genetic polymorphism. Clinically relevant metabolic differences traditionally have been defined by their genotypie expression such as 'poor' and 'extensive' metaboliser. The recent developments of powerful methods for DNA (or genomic) analysis portends a revolutionary expansion of our understanding of physiology as well as pathology. Pharmacogenetics is the study of genetic variation underlying differential response to drugs. Genotyping may become a useful tool in optimising drug treatment. Another part of the genetic research is directed towards the discovery of genetic alterations leading to diseases. Once identified, these genetic alterations can become targets for drug treatment (e.g. gene therapy). Pharmaco-genomics applies the large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism or disease pathway. Table I gives some examples of genetic alterations that are identified together with their effects. Some of these examples will be briefly discussed here.