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Dopamine-β-Hydroxylase Functional Variants

Posted in Biochemical pathways, Cell Biology, Endocrine Diseases, Enzyme Induction, Enzymes and isoenzymes, Gene Regulation, Genomic Expression, Metabolism, Pharmaceutical Discovery, Population genetics, Proteins, Proteomics, Stress Disorders, Translational Science, tagged , , , on March 10, 2016| Leave a Comment »

Dopamine-β-Hydroxylase Functional Variants

Curator: Larry H. Bernstein, MD, FCAP

 

 

Deep sequencing identifies novel regulatory variants in the distal promoter region of the dopamine-β-hydroxylase gene.

Punchaichira TJ1, Prasad S, Deshpande SN, Thelma BK.
Pharmacogenet Genomics. 2016 Mar 9     http://www.ncbi.nlm.nih.gov/pubmed/26959714

OBJECTIVE:

Dopamine-β-hydroxylase (DBH), an enzyme that converts dopamine into norepinephrine, is a drug target in cardiovascular and neuropsychiatric disorders. We aimed to identify functional variants in this gene by deep sequencing and enzyme phenotyping in an Indian cohort.

MATERIALS AND METHODS:

Targeted resequencing of 12 exons and 10 kb upstream sequences of DBH in healthy volunteers (n=50) was performed using the Ion Personal Genome Machine System. Enzyme quantity and activity in their sera samples were determined by ELISA and ultra performance liquid chromatography, respectively. The association of markers with phenotypes was determined using Matrix eQTL. Global P-values for haplotypes generated using UNPHASED 3.1.5 were graphed using GrASP v.082 beta.

RESULTS:

Of the 49 variants identified, nine were novel (minor allele frequency≥0.01). Though individual markers associated with enzyme quantity did not withstand multiple corrections, a novel distal promoter block driven by rs113249250 (global P=1.5×10) was associated. Of the nine single nucleotide polymorphisms (SNPs) associated with enzyme activity, rs3025369, rs1076151 and rs1611115, all from the upstream region, withstood false discovery rate correction (false discovery rate=0.03, 0.03 and 2.9×10, respectively). Conditioning for rs1611115 identified rs1989787 also to affect activity. Importantly, we report an association of a novel haplotype block distal to rs1076151 driven by rs3025369 (global P=8.9×10) with enzyme activity. This regulatory SNP explained 4.9% of the total 46.1% of variance in DBH activity caused by associated SNPs.

CONCLUSION:

This first study combining deep sequencing and enzyme phenotyping identified yet another regulatory SNP suggesting that regulatory variants may be central in the physiological or metabolic role of this gene of therapeutic and pharmacological relevance.

 

 

Correlation of plasma dopamine beta-hydroxylase activity with polymorphisms in DBH gene: a study on Eastern Indian population.

Bhaduri N1, Mukhopadhyay K.
Cell Mol Neurobiol. 2008 May;28(3):343-50.    http://dx.doi.org:/10.1007/s10571-007-9256-8
Plasma dopamine beta-hydroxylase activity (plDbetaH) is tightly regulated by the DBH gene and several genetic polymorphisms have been found to independently exert their influence. In the present investigation, association of four DBH polymorphisms, DBH-STR, rs1611115, rs1108580, and rs2519152 with plDbetaH was examined in blood samples from 100 unrelated individuals belonging to the state of West Bengal, Eastern India. Genotypes obtained after PCR amplification and restriction digestion were used for statistical analyses. plDbetaH was measured using a photometric assay and its correlation with the genetic polymorphisms was analyzed using analysis of variance and linear regression. Moderate linkage disequilibrium (LD) was observed between DBH-STR and rs1611115, while rs1108580 and rs2519152 were in strong LD. ‘T’ allele of rs1611115 showed strong negative correlation with plDbetaH, whereas DBH-STR, rs1108580 and rs2519152 had no major effect. Four haplotypes showed significant influence on plDbetaH. This is the first report on the effect of genetic polymorphisms on plDbetaH from the Indian sub-continent. rs1611115 was the only polymorphism that showed substantial control over plDbetaH. Other polymorphisms which did not show individual effects could possibly be part of larger haplotype blocks that carry the functional polymorphisms controlling plDbetaH.
Polymorphisms and low plasma activity of dopamine-beta-hydroxylase in ADHD children.
Kopecková M1, Paclt I, Goetz P.
Neuro Endocrinol Lett. 2006 Dec;27(6):748-54     http://www.ncbi.nlm.nih.gov/pubmed/17187001
Attention-deficit Hyperactivity disorder (ADHD) is a multifactorial disorder clinically characterized by inattentiveness, impulsivity and hyperactivity. The occurrence of this disorder is between 3 and 6% of the children population, with boys predominating over girls at a ratio of 3:1 or more. The research of some candidate genes (DRD4, DAT, DRD5, DBH, 5HTT, HTR1B and SNAP25) brought consistent results confirming the heredity of ADHD syndromes. Dopamine-beta-hydroxylase (DBH) is an enzyme responsible for the conversion of dopamine into noradrenaline. Alteration of the dopamine/noradrenaline levels can result in hyperactivity. The DBH protein is released in response to stimulation. DBH activity, derived largely from sympathetic nerves, can be measured in human plasma. Patients with ADHD showed decreased activities of DBH in serum and urine. Low DBH levels correlate indirectly with the seriousness of the hyperkinetic syndrome in children [19,20]. In the DBH gene, the G444A, G910T, C1603T, C1912T, C-1021T, 5 -ins/del and TaqI polymorphisms occur frequently and may affect the function of gene products or modify gene expression and thus influence the progression of ADHD. This article reviews the DBH itself and polymorphisms in the DBH gene that influence the DBH activity in the serum and the CSF level of DBH. All those are evaluated in connection with ADHD.
Candidate gene studies of attention-deficit/hyperactivity disorder.
Faraone SV1, Khan SA.
J Clin Psychiatry. 2006;67 Suppl 8:13-20.   http://www.ncbi.nlm.nih.gov/pubmed/16961425
A growing body of behavioral and molecular genetics literature has indicated that the development of attention-deficit/hyperactivity disorder (ADHD) may be attributed to both genetic and environmental factors. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. Molecular genetic studies suggest that the genetic architecture of ADHD is complex, while the handful of genome-wide scans conducted thus far is not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the 8 genes for which the same variant has been studied in 3 or more case-control or family-based studies, 7 show statistically significant evidence of association with ADHD based on pooled odds ratios across studies: the dopamine D4 receptor gene (DRD4), the dopamine D5 receptor gene (DRD5), the dopamine transporter gene (DAT), the dopamine beta-hydroxylase gene (DBH), the serotonin transporter gene (5-HTT), the serotonin receptor 1B gene (HTR1B), and the synaptosomal-associated protein 25 gene (SNAP25). Recent pharmacogenetic studies have correlated treatment nonresponse with particular gene markers, while preclinical studies have increased our understanding of gene expression paradigms and potential analogs for human trials. This literature review discusses the relevance and implications of genetic associations with ADHD for clinical practice and future research
Lack of significant association between -1021C–>T polymorphism in the dopamine beta hydroxylase gene and attention deficit hyperactivity disorder.
Bhaduri N1, Mukhopadhyay K
Neurosci Lett. 2006 Jul 10;402(1-2):12-6     http://www.ncbi.nlm.nih.gov/pubmed/16616989
Recent trends in medications for attention deficit hyperactivity disorder (ADHD) suggest that norepinephrine (NE) deficiency may contribute to the disease etiology. Dopamine beta hydroxylase (DBH) is the key enzyme which converts dopamine to NE and since DBH gene is considered a major quantitative trait locus for plasma DBH activity, genetic polymorphism may lead to altered NE neurotransmission. Several polymorphisms including a 5′ flanking -1021C–>T polymorphism, was reported to be associated with changed DBH activity and an association between -1021C–>T polymorphism with ADHD was observed in Han Chinese children. We have carried out family-based studies with three polymorphisms in the DBH gene, -1021C–>T polymorphism, exon 2*444g/a and intron 5 TaqI RFLP, to explore their association with Indian ADHD cases. Allele and genotype frequency of these polymorphisms in ADHD cases were compared with that of their parents and a control group. Haplotypes obtained were analyzed for linkage disequilibrium (LD). Haplotype-based haplotype relative risk analysis and transmission disequilibrium test showed lack of significant association between transmission of the polymorphisms and ADHD. A haplotype comprising of allele 1 of all polymorphisms showed a slight positive trend towards transmission from parents to ADHD probands. Strong LD was observed between *444g/a and TaqI RFLP in all the groups. However, low D’ values and corresponding log of odds scores in the control group as compared to the ADHD families indicated that, the incidence of the two polymorphisms being transmitted together could be higher in ADHD families.
Association of the dopamine beta hydroxylase gene with attention deficit hyperactivity disorder: genetic analysis of the Milwaukee longitudinal study.
Smith KM1, Daly M, Fischer M, Yiannoutsos CT, Bauer L, Barkley R, Navia BA.
Am J Med Genet B Neuropsychiatr Genet. 2003 May 15;119B(1):77-85.    http://www.ncbi.nlm.nih.gov/pubmed/12707943
Attention deficit hyperactivity disorder (ADHD) is a highly heritable and common disorder that partly reflects disturbed dopaminergic function in the brain. Recent genetic studies have shown that candidate genes involved in dopamine signaling and metabolism contribute to ADHD susceptibility. We have initiated genetic studies in a unique cohort of 158 ADHD and 81 control adult subjects who have been followed longitudinally since childhood in the Milwaukee study of ADHD. From this cohort, genetic analysis was performed in 105 Caucasian subjects with ADHD and 68 age and ethnicity-matched controls for the DRD4 exon 3 VNTR, the SLC6A3 (DAT1) 3′ UTR VNTR, dopamine beta hydroxylase (DBH) TaqI A polymorphism, and the DBH GT microsatellite repeat polymorphism that has been quantitatively associated with serum levels of DBH activity, but not previously studied in ADHD. Results indicate a significant association between the DBH TaqI A1 allele and ADHD (P = 0.018) with a relative risk of 1.33. The DBH GT repeat 4 allele, which is associated with high serum levels of DBH, occurred more frequently in the ADHD group than controls, but the difference did not reach statistical significance. Associations were not found with the SLC6A3 10 repeat or DRD4 7 repeat alleles. These results indicate that the DBH TaqI A allele, or another polymorphism in linkage disequilibrium with this allele, may confer increased susceptibility towards ADHD.
Polymorphisms of the dopamine transporter gene: influence on response to methylphenidate in attention deficit-hyperactivity disorder.
Roman T1, Rohde LA, Hutz MH.
Am J Pharmacogenomics. 2004;4(2):83-92.   http://www.ncbi.nlm.nih.gov/pubmed/15059031
Attention deficit-hyperactivity disorder (ADHD) is a very common and heterogeneous childhood-onset psychiatric disorder, affecting between 3% and 5% of school age children worldwide. Although the neurobiology of ADHD is not completely understood, imbalances in both dopaminergic and noradrenergic systems have been implicated in the origin and persistence of core symptoms, which include inattention, hyperactivity, and impulsivity. The role of a genetic component in its etiology is strongly supported by genetic studies, and several investigations have suggested that the dopamine transporter gene (DAT1; SLC6A3 locus) may be a small-effect susceptibility gene for ADHD. Stimulant medication has a well-documented efficacy in reducing ADHD symptoms. Methylphenidate, the most prescribed stimulant, seems to act mainly by inhibiting the dopamine transporter protein and dopamine reuptake. In fact, its effect is probably related to an increase in extracellular levels of dopamine, especially in brain regions enriched in this protein (i.e. striatum). It is also important to note that dopamine transporter densities seem to be particularly elevated in the brain of ADHD patients, decreasing after treatment with methylphenidate. Altogether, these observations suggest that the dopamine transporter does play a major role in ADHD. Among the several polymorphisms already described in the SLC6A3 locus, a 40 bp variable number of tandem repeats (VNTR) polymorphism has been extensively investigated in association studies with ADHD. Although there are some negative results, the findings from these reports indicate the allele with ten copies of the 40 bp sequence (10-repeat allele) as the risk allele for ADHD. Some investigations have suggested that this polymorphism can be implicated in dopamine transporter gene expression in vitro and dopamine transporter density in vivo, even though it is located in a non-coding region of the SLC6A3 locus. Despite all these data, few studies have addressed the relationship between genetic markers (specifically the VNTR) at the SLC6A3 locus and response to methylphenidate in ADHD patients. A significant effect of the 40 bp VNTR on response to methylphenidate has been detected in most of these reports. However, the findings are inconsistent regarding both the allele (or genotype) involved and the direction of this influence (better or worse response). Thus, further investigations are required to determine if genetic variation due to the VNTR in the dopamine transporter gene is able to predict different levels of clinical response and palatability to methylphenidate in patients with ADHD, and how this information would be useful in clinical practice.
Pharmacogenomics in psychiatry: the relevance of receptor and transporter polymorphisms.
Reynolds GP1, McGowan OO, Dalton CF.
Br J Clin Pharmacol. 2014 Apr;77(4):654-72.    http://dx.doi.org:/10.1111/bcp.12312
The treatment of severe mental illness, and of psychiatric disorders in general, is limited in its efficacy and tolerability. There appear to be substantial interindividual differences in response to psychiatric drug treatments that are generally far greater than the differences between individual drugs; likewise, the occurrence of adverse effects also varies profoundly between individuals. These differences are thought to reflect, at least in part, genetic variability. The action of psychiatric drugs primarily involves effects on synaptic neurotransmission; the genes for neurotransmitter receptors and transporters have provided strong candidates in pharmacogenetic research in psychiatry. This paper reviews some aspects of the pharmacogenetics of neurotransmitter receptors and transporters in the treatment of psychiatric disorders. A focus on serotonin, catecholamines and amino acid transmitter systems reflects the direction of research efforts, while relevant results from some genome-wide association studies are also presented. There are many inconsistencies, particularly between candidate gene and genome-wide association studies. However, some consistency is seen in candidate gene studies supporting established pharmacological mechanisms of antipsychotic and antidepressant response with associations of functional genetic polymorphisms in, respectively, the dopamine D2 receptor and serotonin transporter and receptors. More recently identified effects of genes related to amino acid neurotransmission on the outcome of treatment of schizophrenia, bipolar illness or depression reflect the growing understanding of the roles of glutamate and γ-aminobutyric acid dysfunction in severe mental illness. A complete understanding of psychiatric pharmacogenomics will also need to take into account epigenetic factors, such as DNA methylation, that influence individual responses to drugs.
Pharmacogenetics of psychotropic drug response.
Malhotra AK1, Murphy GM Jr, Kennedy JL.
Am J Psychiatry. 2004 May;161(5):780-96    http://www.ncbi.nlm.nih.gov/pubmed/15121641http://dx.doi.org/10.1176/appi.ajp.161.5.780

OBJECTIVE:

Molecular genetic approaches provide a novel method of dissecting the heterogeneity of psychotropic drug response. These pharmacogenetic strategies offer the prospect of identifying biological predictors of psychotropic drug response and could provide the means of determining the molecular substrates of drug efficacy and drug-induced adverse events.

METHOD:

The authors discuss methods issues in executing pharmacogenetic studies, review the first generation of pharmacogenetic studies of psychotropic drug response, and consider future directions for this rapidly evolving field.

RESULTS:

Pharmacogenetics has been most commonly used in studies of antipsychotic drug efficacy, antidepressant drug response, and drug-induced adverse effects. Data from antipsychotic drug studies indicate that polymorphisms within the serotonin 2A and dopamine receptor 2 genes may influence drug efficacy in schizophrenia. Moreover, a growing body of data suggests a relationship between the serotonin transporter gene and clinical effects of the selective serotonin reuptake inhibitors used to treat depression. A significant relationship between genetic variation in the cytochrome P450 system and drug-induced adverse effects may exist for certain medications. Finally, a number of independent studies point to a significant effect of a dopamine D(3) receptor polymorphism on susceptibility to tardive dyskinesia.

CONCLUSIONS:

Initial research into the pharmacogenetics of psychotropic drug response suggests that specific genes may influence phenotypes associated with psychotropic drug administration. These results remain preliminary and will require further replication and validation. New developments in molecular biology, human genomic information, statistical methods, and bioinformatics are ongoing and could pave the way for the next generation of pharmacogenetic studies in psychiatry.

OBJECTIVE: Molecular genetic approaches provide a novel method of dissecting the heterogeneity of psychotropic drug response. These pharmacogenetic strategies offer the prospect of identifying biological predictors of psychotropic drug response and could provide the means of determining the molecular substrates of drug efficacy and drug-induced adverse events. METHOD: The authors discuss methods issues in executing pharmacogenetic studies, review the first generation of pharmacogenetic studies of psychotropic drug response, and consider future directions for this rapidly evolving field. RESULTS: Pharmacogenetics has been most commonly used in studies of antipsychotic drug efficacy, antidepressant drug response, and drug-induced adverse effects. Data from antipsychotic drug studies indicate that polymorphisms within the serotonin 2A and dopamine receptor 2 genes may influence drug efficacy in schizophrenia. Moreover, a growing body of data suggests a relationship between the serotonin transporter gene and clinical effects of the selective serotonin reuptake inhibitors used to treat depression. A significant relationship between genetic variation in the cytochrome P450 system and drug-induced adverse effects may exist for certain medications. Finally, a number of independent studies point to a significant effect of a dopamine D3 receptor polymorphism on susceptibility to tardive dyskinesia. CONCLUSIONS: Initial research into the pharmacogenetics of psychotropic drug response suggests that specific genes may influence phenotypes associated with psychotropic drug administration. These results remain preliminary and will require further replication and validation. New developments in molecular biology, human genomic information, statistical methods, and bioinformatics are ongoing and could pave the way for the next generation of pharmacogenetic studies in psychiatry.

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A Reconstructed View of Personalized Medicine

Posted in Amino acids, Anaerobic Glycolysis, Apoptosis, Autophagy, Biochemical pathways, Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Cell death pathways, Curation, Disease Biology, DNA repair, Enzymes and isoenzymes, Gene Regulation and Evolution, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genome Biology, Genomic Expression, Human aging, Metabolism, Metabolomics, Micronutrients, Nitric Oxide in Health and Disease, Nutrition, Pharmaceutical Analytics, Pharmaceutical Discovery, Protein-energy malnutrition, Proteins, Proteomics, Pyridine nucleotides, Pyruvate Kinase, RNA Biology, Signaling, Signaling & Cell Circuits, Stress Disorders, Ubiquitinylation, Warburg effect, tagged , , , , , , , , , , on February 26, 2016| Leave a Comment »

A Reconstructed View of Personalized Medicine

Author: Larry H. Bernstein, MD, FCAP

 

There has always been Personalized Medicine if you consider the time a physician spends with a patient, which has dwindled. But the current recognition of personalized medicine refers to breakthrough advances in technological innovation in diagnostics and treatment that differentiates subclasses within diagnoses that are amenable to relapse eluding therapies.  There are just a few highlights to consider:

  1. We live in a world with other living beings that are adapting to a changing environmental stresses.
  2. Nutritional resources that have been available and made plentiful over generations are not abundant in some climates.
  3. Despite the huge impact that genomics has had on biological progress over the last century, there is a huge contribution not to be overlooked in epigenetics, metabolomics, and pathways analysis.

A Reconstructed View of Personalized Medicine

There has been much interest in ‘junk DNA’, non-coding areas of our DNA are far from being without function. DNA has two basic categories of nitrogenous bases: the purines (adenine [A] and guanine [G]), and the pyrimidines (cytosine [C], thymine [T], and  no uracil [U]),  while RNA contains only A, G, C, and U (no T).  The Watson-Crick proposal set the path of molecular biology for decades into the 21st century, culminating in the Human Genome Project.

There is no uncertainty about the importance of “Junk DNA”.  It is both an evolutionary remnant, and it has a role in cell regulation.  Further, the role of histones in their relationship the oligonucleotide sequences is not understood.  We now have a large output of research on noncoding RNA, including siRNA, miRNA, and others with roles other than transcription. This requires major revision of our model of cell regulatory processes.  The classic model is solely transcriptional.

  • DNA-> RNA-> Amino Acid in a protein.

Redrawn we have

  • DNA-> RNA-> DNA and
  • DNA->RNA-> protein-> DNA.

Neverthess, there were unrelated discoveries that took on huge importance.  For example, since the 1920s, the work of Warburg and Meyerhoff, followed by that of Krebs, Kaplan, Chance, and others built a solid foundation in the knowledge of enzymes, coenzymes, adenine and pyridine nucleotides, and metabolic pathways, not to mention the importance of Fe3+, Cu2+, Zn2+, and other metal cofactors.  Of huge importance was the work of Jacob, Monod and Changeux, and the effects of cooperativity in allosteric systems and of repulsion in tertiary structure of proteins related to hydrophobic and hydrophilic interactions, which involves the effect of one ligand on the binding or catalysis of another,  demonstrated by the end-product inhibition of the enzyme, L-threonine deaminase (Changeux 1961), L-isoleucine, which differs sterically from the reactant, L-threonine whereby the former could inhibit the enzyme without competing with the latter. The current view based on a variety of measurements (e.g., NMR, FRET, and single molecule studies) is a ‘‘dynamic’’ proposal by Cooper and Dryden (1984) that the distribution around the average structure changes in allostery affects the subsequent (binding) affinity at a distant site.

What else do we have to consider?  The measurement of free radicals has increased awareness of radical-induced impairment of the oxidative/antioxidative balance, essential for an understanding of disease progression.  Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Various studies have confirmed that metals activate signaling pathways and the carcinogenic effect of metals has been related to activation of mainly redox sensitive transcription factors, involving NF-kappaB, AP-1 and p53.

I have provided mechanisms explanatory for regulation of the cell that go beyond the classic model of metabolic pathways associated with the cytoplasm, mitochondria, endoplasmic reticulum, and lysosome, such as, the cell death pathways, expressed in apoptosis and repair.  Nevertheless, there is still a missing part of this discussion that considers the time and space interactions of the cell, cellular cytoskeleton and extracellular and intracellular substrate interactions in the immediate environment.

There is heterogeneity among cancer cells of expected identical type, which would be consistent with differences in phenotypic expression, aligned with epigenetics.  There is also heterogeneity in the immediate interstices between cancer cells.  Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. In the case of breast cancer, there is interaction with estrogen , and we refer to an androgen-unresponsive prostate cancer.

Finally,  the interaction between enzyme and substrates may be conditionally unidirectional in defining the activity within the cell.  The activity of the cell is dynamically interacting and at high rates of activity.  In a study of the pyruvate kinase (PK) reaction the catalytic activity of the PK reaction was reversed to the thermodynamically unfavorable direction in a muscle preparation by a specific inhibitor. Experiments found that in there were differences in the active form of pyruvate kinase that were clearly related to the environmental condition of the assay – glycolitic or glyconeogenic. The conformational changes indicated by differential regulatory response were used to present a dynamic conformational model functioning at the active site of the enzyme. In the model, the interaction of the enzyme active site with its substrates is described concluding that induced increase in the vibrational energy levels of the active site decreases the energetic barrier for substrate induced changes at the site. Another example is the inhibition of H4 lactate dehydrogenase, but not the M4, by high concentrations of pyruvate. An investigation of the inhibition revealed that a covalent bond was formed between the nicotinamide ring of the NAD+ and the enol form of pyruvate.  The isoenzymes of isocitrate dehydrogenase, IDH1 and IDH2 mutations occur in gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. In this case, there is steric hindrance by Asp279 where the isocitrate substrate normally forms hydrogen bonds with Ser94.

Personalized medicine has been largely viewed from a lens of genomics.  But genomics is only the reading frame.  The living activities of cell processes are dynamic and occur at rapid rates.  We have to keep in mind that personalized in reference to genotype is not complete without reconciliation of phenotype, which is the reference to expressed differences in outcomes.

 

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A Perspective on Personalized Medicine

Posted in Personalized and Precision Medicine & Genomic Research, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Rapid automation of plasma protein pools, tagged , , , , , , on February 22, 2016| Leave a Comment »

A Perspective on Personalized Medicine

Curator: Larry H. Bernstein, MD, FCAP

 

 

A book has recently been reviewed by Laura Fisher (Feb 19 2016) titled “Junk DNA: a journey through the dark matter of the genome” (Nessa Carey  Icon Books 2015 | 352pp  ISBN 9781848319158).  http://www.rsc.org/chemistryworld/2016/02/junk-dna-genome-nessa-carey-book-review  It is important in its focus on, ‘junk DNA’, a term coined in the 1960s that refers to regions of our DNA that don’t code for proteins.  It is now known that a large portion of the genome is noncoding. These non-coding areas of our DNA are far from being without function. Whether regulating gene expression and transcription, or providing protein attachment sites, this once-dismissed part of the genome is vital for all life, and this is the focus of Junk DNA.  However, in 1869 Friedrich Miescher discovered a new substance (Dahm, 2008) from the cell nuclei that had chemical properties unlike any protein, including a much higher phosphorous content and resistance to proteolysis (protein digestion).  He wrote, “It seems probable to me that a whole family of such slightly varying phosphorous-containing substances will appear, as a group of nucleins, equivalent to proteins” (Wolf, 2003). In 1971, Chargaff  noted that Miescher’s discovery of nucleic acids was unique among the discoveries of the four major cellular components (i.e., proteins, lipids, polysaccharides, and nucleic acids) in that it could be “dated precisely… [to] one man one place, one date.”  We now know that there are two basic categories of nitrogenous bases: the purines (adenine [A] and guanine [G]), each with two fused rings, and the pyrimidines (cytosine [C], thymine [T], and uracil [U]), each with a single ring. Furthermore, it is now widely accepted that RNA contains only A, G, C, and U (no T), whereas DNA contains only A, G, C, and T (no U).  Keeping this in mind, the Watson-Crick proposal, as important as it was, was a discovery out of historical proportion, and it set the path of molecular biology for the remainder of the 20th century. A consequence of this seminal event was that the direction of biochemistry and molecular biology became set for several generations into the 21st century, culminating in the Human Genome Project.

As important as this discovery and others related that followed, there were a number of unrelated discoveries that took on huge importance, immediately recognized, but not so soon integrated with the evolving body of knowledge.  For example, since the 1920s, the work of Warburg and Meyerhoff, followed by that of Krebs, Kaplan, Chance, and others built a solid foundation in the knowledge of enzymes, coenzymes, adenine and pyridine nucleotides, and metabolic pathways, not to mention the importance of Fe3+, Cu2+, Zn2+, and other metal cofactors.  There was also a relevance of the work of Jacob, Monod and Changeux, and the effects of cooperativity in allosteric systems and of repulsion in tertiary structure of proteins related to hydrophobic and hydrophilic interactions. This involves the effect of one ligand on the binding or catalysis of another with no direct interaction between the two ligands. This was demonstrated by the end-product inhibition of the enzyme, L-threonine deaminase (Changeux 1961), L-isoleucine, which differs sterically from the reactant, L-threonine whereby binding at a different, nonoverlapping (regulatory) site, the former could inhibit the enzyme without competing with the latter. Pauling (Pauling 1935) had earlier proposed a model for intramolecular control in hemoglobin to explain the positive cooperativity observed in the binding of oxygen molecules. But  Monod, Wyman, and Changeux  substantially updated the view of allostery in 1965 with their landmark paper.  Present day applications of computational methods to biomolecular systems, combined with structural, thermodynamic, and kinetic studies, make possible an approach to that question, so as to provide a deeper understanding of the requirements for allostery. The current view is that a variety of measurements (e.g., NMR, FRET, and single molecule studies) are providing additional data beyond that available previously from structural, thermodynamic, and kinetic results. These should serve to continue to improve our understanding of the molecular mechanism of allostery, particularly when supplemented by simulations and theoretical analyses. A ‘‘dynamic’’ proposal by Cooper and Dryden (1984) is that the distribution around the average structure changes in allostery; which in turn, affects the subsequent (binding) affinity at a distant site. Such a model focuses on the vibrational contribution to the entropy as the origin of cooperativity, as discussed for the CAPN dimer.  Why is this important?  It is because it brings a different focus into the conception of how living cells engage with their neighbors and external environment.  Moreover, this is not all that has to be considered.

What else do we have to consider?  Oxidative stress is essentially an imbalance between the production of free radicals and the ability of the body to counteract or detoxify their harmful effects through neutralization by antioxidants. The measurement of free radicals has increased awareness of radical-induced impairment of the oxidative/antioxidative balance, essential for an understanding of disease progression.  Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Common mechanisms involving the Fenton reaction, generation of the superoxide radical and the hydroxyl radical appear to be involved for iron, copper, chromium, vanadium and cobalt primarily associated with mitochondria, microsomes and peroxisomes. Various studies have confirmed that metals activate signaling pathways and the carcinogenic effect of metals has been related to activation of mainly redox sensitive transcription factors, involving NF-kappaB, AP-1 and p53.

In addition to what I have identified, there is substantial work in the last decade to indicate a more complex model of cellular regulatory processes.  On the one hand, there is no uncertainty about the importance of “Junk DNA”.  Indeed, not only is “Junk DNA” not junk, but it has either a presence that is an evolutionary remnant, or it has a role in cell regulation, much of which has yet to be understood.  Moreover, the relationship between the oligonucleotide sequences to their histones are largely unknown.  Beyond the DNA sequences, the language of the gene, we now have a large output of research on noncoding RNA.  We now have siRNA, miRNA, and others with roles other than transcription. This is a very active field of investigation that requires major revision of our model of cell regulatory processes.  The classic model is solely transcriptional.  DNA-> RNA-> Amino Acid in a protein.  This would now have to be redrawn because DNA-> RNA-> DNA and DNA->RNA-> protein-> DNA.

I have provided a series of four mechanisms explanatory for transcription and for regulation of the cell. This is not adequate for a more full comprehension because there is a layer beyond the classic model of metabolic pathways associated with the cytoplasm, mitochondria, endoplasmic reticulum, and lysosome, there are critical paths beyond oxidative phosphorylation and glycolysis, such as the cell death pathways, expressed in a homeostasis between apoptosis and repair.  Nevertheless, there is still a missing part of this discussion. The missing piece gets at the time and space interactions of the cell, cellular cytoskeleton and extracellular and intracellular substrate interactions in the immediate environment.  This can’t be simply accounted for by genetics or epigenetics. There have been papers that call attention to heterogeneity among cancer cells of expected identical type, which would be consistent with differences in phenotypic expression, aligned with epigenetics.  There is now the recent publication of the finding that there is heterogeneity in the immediate interstices between cancer cells, which may seem surprising, but it should not be.  This refers to the complexity of the cells arranged as tissues and to their immediate environment, which I shall elaborate on. Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. I did introduce the word gene into this reference, and we are well aware of mutations that occur in cancer progression.  In the case of breast cancer, mention is not made of interaction with a hormone, as we refer to in androgen-unresponsive prostate cancer.  This is particularly relevant, but incomplete.

The fifth item for discussion is the interaction between enzyme and substrates that may be conditionally unidirectional in defining the activity within the cell.  When we speak of the genome, we are dealing with a code defined by an oligonucleotide sequence that has an element of stability, but that can conditionally be altered by a process termed mutagenesis.  The altered code can be expected to have a negative, positive, or no effect, depending. In any case, there is a substantial stability inherent in the code that is essential to all living creatures.  The activity of the cell is dynamically interacting and at high rates of activity.  There are many examples of this.  The first example is in a study of energy for reverse pyruvate kinase (PK) reaction.  This catalytic activity of the PK reaction was reversed to the thermodynamically unfavorable direction in a muscle preparation by a specific inhibitor. Using the same crude supernatant for the two opposite activities of this enzyme some of the results found in the regulatory assays indicated differences in the active form of pyruvate kinase that were clearly related to the environmental condition – glycolitic or glyconeogenetic – of the assay. The conformational changes indicated by differential regulatory response found in the conditions studied, together with the role of similar factors, for instance, substrates and pH, in the structural states proposed by others, were used together to present a dynamic conformational model functioning at the active site of the enzyme. In the model, the interaction of the enzyme active site with its substrates is described according to its vibrational, translational and rotational components and the activating ions – induced increase in the vibrational energy levels of the active site decreases the energetic barrier for substrate induced changes at the site.

Another example is the pyridine nucleotide-linked dehydrogenases.   The lactate dehydrogenase (LD) reaction is ordered so that NADH binds to the enzyme before pyruvate can bind. The H-type isoenzyme, but not the M-type, is characterized by substrate inhibition at high pyruvate concentrations. The inhibition of the H4 lactate dehydrogenase, but not the M4, by high concentrations of pyruvate is caused by the formation of an abortive complex consisting of the enzyme, pyruvate, and NADH. An investigation of the structural properties of the ternary complex revealed that the complex possesses an absorption maximum at 335 nm and that a covalent bond was formed between the nicotinamide ring of the NAD+ and the pyruvate moiety. The same study demonstrated that the enol form of pyruvate is responsible for the complex formation.  It was suggested that abortive complex formation is a significant metabolic control mechanism, and the different behavior of the H and M forms has been rationalized in terms of different functional roles for the two isoenzymes.  However, similar experiments carried out with the mitochondrial malate dehydrogenase suggested a similar inhibition, but in this case only the mitochondrial malate dehydrogenase is sensitive to inhibition by high concentrations of oxaloacetate. Further studies showed the inhibition is promoted by an abortive binary complex formed by the enzymes and the enol form of oxalacetate. Neither the oxidized coenzyme nor the reduced coenzyme appears to be involved in the formation of this complex. These results suggest that the mechanism of substrate inhibition that occurs with the pig heart malate dehydrogenases is different from that observed with the lactate dehydrogenases.

It was established years later that there is an isoenzyme of isocitrate dehydrogenase that is characteristic for cancer cells. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2–4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are heterozygous in cancer, and they catalyze the production of α-2-hydroxyglutarate. The study found human IDH1 transitions between an inactive open, an inactive semi-open, and a catalytically active closed conformation. In the inactive open conformation, Asp279 occupies the position where the isocitrate substrate normally forms hydrogen bonds with Ser94. This steric hindrance by Asp279 to isocitrate binding is relieved in the active closed conformation.

Finally, what does this have to do with personalized medicine? Personalized medicine has been largely view from a lens of genomics.  But genomics is only the reading frame, even taking into consideration the mutations that are found in transition.  The living activities of cell processes are dynamic and occur at rapid rates.  When we refer to homeostasis and to neoplasia, we have to keep in mind that personalized in reference to genotype is not complete without reconciliation of phenotype, which is the reference to expressed differences in outcomes.

References

Cui Q& Karplus M. Allostery and cooperativity revisited. Protein Science 2008; 17:1295–1307. http://www.proteinscience.org/cgi/doi/10.1110/ps.03259908.

Changeux, J-P. 1961. The feedback control mechanisms of biosynthetic L-threonine deaminase by L-isoleucine. Cold Spring Harb. Symp. Quant. Biol. 26: 313–318.

Pauling, L. 1935. The oxygen equilibrium of hemoglobin and its structural interpretation. Proc. Natl. Acad. Sci. 21: 181–191.

Monod, J., Wyman, J., and Changeux, J.P. 1965. On the nature of allosteric transitions: A plausible model. J. Mol. Biol. 12: 88–118.

Cooper, A. and Dryden, D.T.F. 1984. Allostery without conformational change. Eur. Biophys. J. 11: 103–109.

Valko M, Morris H and Cronin TD. Toxicity and Oxidative Stress. Curr Med Chem 2005; 12(10):1161-208
http://dx.doi.org:/10.2174/0929867053764635

Natrajan R, Sailem H, Mardakheh FK, Arias Garcia M, Tape CJ, Dowsett M, etal.(2016) Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis. PLoS Med 13(2):e1001961. http://dx.doi.org:/10.1371/journal.pmed.1001961

Roselino JEDS, Xavier AR, Kettelhut IDC, Hélios Migliorini RH. Res Gate communication2015.
http://dx.doi.org:/10.13140/RG.2.1.5137.1686

O’Carra P, Barry S and Corcoran E. Affinity Chromatographic Differentiation of Lactate Dehydrogenase Isoenzymes on the Basis of Differential Abortive Complex Formation.  FEBS Letters 1974; 43(2):163-168.

Everse J, Berger RL, and Kaplan N0 (1972) in Structure and Function of Oxidation-Reduction Enzymes (Akeson A, and Ehrenberg A, eds) pp. 691-708, Pergamon Press, Oxford.

LH Bernstein LH, Grisham MB, Cole KD, and Everse J. Substrate Inhibition of the Mitochondrial and Cytoplasmic Malate Dehydrogenases. J Biol Chem 1978 Dec 25; 253(24):8697-8701.

Reitman ZJ & Yan H. Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism. J Natl Cancer Inst 2010; 102: 1–10. http://dx.doi.org:/10.1093/jnci/djq187

 

 

 

 

 

 

 

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New anti-Malarial treatment

Posted in Advanced Drug Manufacturing Technology, Antimalarial Preparation, Bacterial Resistance, Cell Biology, Chemical Genetics, Clinical & Translational, Curation, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genomics Pharmacy, Malaria, Parasitology, Pharmaceutical Discovery, Proteosome, tagged , , on February 11, 2016| Leave a Comment »

New anti-Malarial treatment

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Malaria Proteasome Inhibitors Could Reverse Parasite Drug Resistance

http://www.genengnews.com/gen-news-highlights/malaria-proteasome-inhibitors-could-reverse-parasite-drug-resistance/81252358/

 

http://www.genengnews.com/Media/images/GENHighlight/thumb_108676_web2680362491.jpg

This structure (bottom left) of the malaria parasite’s proteasome, obtained using the revolutionary Cryo-Electron Microscopy technique, enabled the design of a specific inhibitor (front) against the mosquito-borne malaria parasite (pictured at back). [University of Melbourne]

 

  • With media attention recently focused on the spread of the Zika virus, it’s easy to forget about the mosquito-borne disease that has been credited with killing one out of every two people who have ever lived—malaria. Currently, close to 50 percent of the world’s population live in malaria-endemic areas, leading to between 200–500 million new cases and close to 500,000 deaths annually (mostly children under the age of five).

    Adding to the complexities of trying to control this disease is that resistance to the most effective antimalarial drug, artemisinin, has developed in Southeast Asia, with fears it will soon reach Africa. Artemisinin-resistant species have spread to six countries in five years.

    A collaborative team of scientists from Stanford University, University of California, San Francisco, University of Melbourne, and the MRC in Cambridge have used cutting-edge technology to design a smarter drug to combat the resistant strain.

    “Artemisinin causes damage to the proteins in the malaria parasite that kill the human cell, but the parasite has developed a way to deal with that damage. So new drugs that work against resistant parasites are desperately needed,” explained coauthor Leann Tilley, Ph.D., professor and deputy head of biochemistry and molecular biology in the Bio21 Molecular Science and Biotechnology Institute at The University of Melbourne.

    Malaria is caused by the protozoan parasite from the genus Plasmodium. Five different species are known to cause malaria in humans, with P. falciparum infection leading to the most deaths. The parasite is transmitted through the bite of the female mosquito and ultimately ends up residing within the host’s red blood cells (RBCs)—replicating and then bursting forth to invade more RBCs in a recurrently timed cycle.

    “This penetration/replication/breakout cycle is rapid—every 48 hours—providing the opportunity for large numbers of mutations that can produce drug resistance,” said senior study author Matthew Bogyo, Ph.D., professor in the department of pathology at Stanford Medical School. “Consequently, several generations of antimalarial drugs have long since been rendered useless.”

    The compound that investigators developed targets the parasites proteasome—a protein degradation pathway that removes surplus or damaged proteins through a cascade of proteolytic reactions.

    “The parasite’s proteasome is like a shredder that chews up damaged or used-up proteins. Malaria parasites generate a lot of damaged proteins as they switch from one life stage to another and are very reliant on their proteasome, making it an excellent drug target,” Dr. Tilley noted.

    The scientists purified the proteasome from the malaria parasite and examined its activity against hundreds of different peptide sequences. From this, they were able to design inhibitors that selectively targeted the parasite proteasome while sparing the human host enzymes.

    The findings from this study were published recently in Nature through an article titled “Structure- and function-based design of Plasmodium-selective proteasome inhibitors.”

    Additionally, scientists at the MRC used a new technique called Single-Particle Cryo-Electron Microscopy to generate a three-dimensional, high-resolution structure of a protein, based on thousands composite images.

    The researchers tested the new drug in red blood cells infected with parasites and found that it was as effective at killing the artemisinin resistant parasites as it was for the sensitive parasites.

    “The compounds we’ve derived can kill artemisinin-resistant parasites because those parasites have an increased need for highly efficient proteasomes,” Dr. Bogyo commented. “So, combining the proteasome inhibitor with artemisinin should make it possible to block the onset of resistance. That will, in turn, allow the continued use of that front-line malaria treatment, which has been so effective up until now.”

    “The new proteasome inhibitors actually complement artemisinin drugs,” Dr. Tilley added. “Artemisinins cause protein damage and proteasome inhibitors prevent the repair of protein damage. A combination of the two provides a double whammy and could rescue the artemisinins as antimalarials, restoring their activity against resistant parasites.”

    The scientists were excited by their results, as they may provide a much-needed strategy to combat the growing levels of resistance for this deadly pathogen. However, the researchers tempered their exuberance by noting that many more drug libraries needed to be screened before clinical trials can begin.

    “The current drug is a good start, but it’s not yet suitable for humans. It needs to be able to be administered orally and needs to last a long time in the blood stream,” Dr. Tilley concluded.

 

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More Than 25 Percent of the Novel New Drugs Approved by FDA in 2015 are Personalized Medicines

Posted in FDA Regulatory Affairs, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Informatics, Pharmaceutical R&D Investment on January 24, 2016| Leave a Comment »

More Than 25 Percent of the Novel New Drugs Approved by FDA in 2015 are Personalized Medicines

Reporter: Aviva Lev-Ari, PhD, RN

A new analysis from the Personalized Medicine Coalition (PMC) documents an upward trend in the number of personalized medicine approvals at FDA, with personalized medicines accounting for more than 1 in 4 novel new drugs (NNDs) approved in 2015.

The analysis, titled 2015 Progress Report: Personalized Medicine at FDA, lists the 13 personalized medicines approved as NNDs in 2015, which represent 28 percent of the 45 NNDs the agency approved overall. The new approvals accelerate a trend PMC first noted in 2014, when the Coalition classified 21 percent of the year’s NNDs as personalized medicines.

PMC Science Policy Vice President Daryl Pritchard, Ph.D., said the momentum is driven by scientific validation of personalized medicine’s ability to improve patient outcomes.

“The scientific community has established personalized medicine as a successful approach to treating many diseases,” Pritchard said. “The increasing number of approvals for these drugs reflects that progress.”

SOURCE

http://www.pharmpro.com/news/2016/01/many-novel-drugs-approved-fda-2015-are-personalized-medicines

 

2015 Progress Report Personalized Medicine at FDA

 

More Than 25 Percent of the Novel New Drugs Approved by FDA in 2015 are Personalized Medicines

The transformation of health care from one-size-fits-all, trial-and-error medicine to a targeted approach utilizing an individual patient’s molecular information continues to accelerate as the U.S. Food and Drug Administration (FDA) more regularly and rapidly approves new personalized medicines. FDA’s Center for Drug Evaluation and Research (CDER) approved 45 novel new drugs (NNDs), either

new molecular entities or new therapeutic biologics, in 2015. Of these 45 NNDs, 13 of them — more than 25 percent — were personalized medicines as classified by the Personalized Medicine Coalition (PMC), thus continuing a trend that began last year when nine of 41 NNDs were classified as personalized medicines.

 

SOURCE

http://www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/2015_Progress_Report_PM_at_FDA.pdf

 

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Applying Pharmacology to New Drug Discovery, April 22, 2016 in San Diego, CA by CHI

Posted in Drug Delivery Platform Technology, Pharmaceutical Analytics, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical R&D Informatics, Pharmaceutical R&D Investment, Pharmacodynamics and Pharmacokinetics, Pharmacogenomics on January 8, 2016| Leave a Comment »

Applying Pharmacology to New Drug Discovery, April 22, 2016 in San Diego, CA by CHI

Reporter: Aviva Lev-Ari, PhD, RN

 

Applying Pharmacology to New Drug Discovery, April 22, 2016 in San Diego, CA by CHI

The system-independent quantification of molecular drug properties for prediction of therapeutic utility

April 22, 2016

Over the past 6 six years, the primary cause of new drug candidate failures (50%) has been failure of therapeutic efficacy. Put another way, drug discovery programs do everything right, get the defined candidate molecule, only to have it fail in therapeutic trials. Among the most prevalent reasons proposed for this shortcoming is the lack of translation of in vitro and recombinant drug activity to therapeutic in vivo whole systems. Drug activity in complete systems can be characterized with the application of pharmacological principles which translate drug behaviors in various organs with molecular scales of affinity and efficacy.

Pharmacological techniques are unique in that they can convert descriptive data (what we see, potency, activity in a given system) to predictive data (molecular scales of activity that can be used to predict activity in all systems including the therapeutic one, i.e. affinity, efficacy). The predicted outcome of this process is a far lower failure rate as molecules are progressed toward clinical testing.

Instructor

Terry Kenakin presently is a Professor of Pharmacology in the Department of Pharmacology, University of North Carolina School of Medicine. The course is taught from the perspective of industrial drug discovery; Dr. Kenakin has worked in drug industry for 32 years (7 at Burroughs-Wellcome, RTP, NC and 25 at GlaxoSmithKline, RTP. NC). He is Editor-in-Chief of the Journal of Receptors and Signal Transduction and Co-Editor-in-Chief of Current Opinion in Pharmacology and is on numerous journal Editorial Boards. In addition, he has authored over 200 peer reviewed papers and reviews and has written 10 books on Pharmacology.

Course Material

Summary sheets, exercises with answers, relevant papers are included as well as a pdf of all slides. The course is based on the book A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery. 4th Edition, Elsevier/Academic Press, 2014.

This course will describe pharmacological principles and procedures to quantify affinity, efficacy, biased signaling and allostery to better screen for new drugs and characterize drug candidates in lead optimization assays.

1. Assay Formats/Experimental Design

  • Binding
  • Functional Assays
  • Null Method Assays

2. Agonism

  • Agonist Affinity/Efficacy
  • Black/Leff Operational model

3. Biased Signaling (Agonism)

  • Mechanism of Biased Signaling
  • Quantifying Biased Agonism
  • Therapeutic application(s)

4. Orthosteric Antagonism (I)

  • Competitive
  • Non-Competitive/Irreversible

5. Orthosteric Antagonism (II)

  • Partial Agonism
  • Inverse Agonism

6. Allosteric Modulation (I)

  • Functional Allosteric Model
  • Negative Allosteric Modulators (NAMs)

7. Allosteric Modulation (II)

  • Positive Allosteric Modulators (PAMs)
  • Allosteric Agonism

8. Drug-Receptor Kinetics

  • Measuring Target Coverage
  • Allosteric Proof-of-Concept
  • Application of Real-Time Kinetics

9. Drug Screening

  • Design of Screening Assays
  • Screening for Allosteric Modulators

Cambridge Healthtech Institute’s Eleventh Annual Drug Discovery Chemistry is a dynamic conference for medicinal chemists working in pharma and biotech. Focused on discovery and optimization challenges of small molecule drug candidates, this event provides many exciting opportunities for scientists to create a unique program by going back and forth between concurrent meeting tracks to hear presentations most suited to one’s personal interests. New for 2016 is the addition of three symposia on Friday covering the blood-brain barrier, biophysical approaches for drug discovery, and antivirals.

Plenary Keynotes

 

A New Model for Academic Translational Research

Peter G. Schultz, Ph.D., The Scripps Research Institute

Cell-Penetrating Miniproteins

Gregory L. Verdine, Ph.D., Harvard University

April 19-20

April 20-21

April 22

Inflammation Inhibitors

Kinase Inhibitor Chemistry

Brain Penetrant Inhibitors

Protein-Protein Interactions

Macrocyclics & Constrained Peptides

Biophysical Approaches

Epigenetic Inhibitor Discovery

Fragment-Based Drug Discovery

Antivirals

Short Courses

Make the most of your time in San Diego by adding on one or more short courses*. Topics include trends in physical properties, GPCRs, peptide therapeutics, immunology, phenotypic screening, crystallography, ligand-receptor molecular interactions, inhibitor design, macrocycles, FBDD, and covalent inhibitors.

* separate registration required for short courses

SOURCE

From: Deborah Shear <pete@healthtech.com>

Date: Friday, January 8, 2016 at 11:42 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Training Seminar: Applying Pharmacology to New Drug Discovery

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J.P. Morgan 34th Annual Healthcare Conference & Biotech Showcase™ January 11 – 15, 2016 in San Francisco

Posted in BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Conference Coverage with Social Media, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genome Biology, Genomic Testing: Methodology for Diagnosis, Global Partnering & Biotech Investment, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Informatics, Pharmaceutical R&D Investment, Venture Capital on January 7, 2016| Leave a Comment »

J.P. Morgan 34th Annual Healthcare Conference & Biotech Showcase™ January 11 – 15, 2016 in San Francisco

Reporter: Aviva Lev-Ari, PhD, RN

J.P. Morgan 34th Annual Healthcare Conference

When:

January 11, 2016 – January 14, 2016 (all-day)

Where:

San Francisco, CA, USA

Conference AGENDA

http://jpmorgan.metameetings.com/confbook/healthcare16/agenda.php 

 

UPDATED on 1/10/2016

The definitive guide to the J.P. Morgan Healthcare Conference

By MEGHANA KESHAVAN Jan 9, 2016 at 2:22 PM

Screen-Shot-JPMOrgan-HC Conference

Image SOURCE

[Image courtesy of Flickr user Ryan McDonald]

http://medcitynews.com/2016/01/the-definitive-guide-to-the-j-p-morgan-healthcare-conference/

 

MAJOR BioTech Conferences in San Francisco –

The CAPITAL of BioTech for 2nd week in January 2016

 

  • Festival Start up Health

http://festival.startuphealth.com/

  • Biotech Showcase 2016

http://www.ebdgroup.com/bts/media/about_conf.php

  • JP Morgan HealthCare Conference

http://globalbiodefense.com/2015/12/28/jp_morgan_healthcare_2016/#sthash.IhPw1DcA.dpuf

AGENDA

#JPM16

http://jpmorgan.metameetings.com/confbook/healthcare16/agenda.php

  • The 9th Annual OneMedForum, San Francisco 2016 – A Private Investment Conference for OneMed Research Clients

http://www.onemedconferences.com/

 

  • RESI@JPM — Redefining Early Stage Investments – Life Science Nation (LSN)

http://www.resiconference.com/

 

Venture Valkyrie (and capitalist) Lisa Suennen rightly pointed out that JPM is typically a male-dominated affair, which is why she’s written “JP Morgan: Where the Boys are… And not the Girls.”

In a field where women hold many senior positions in actual US healthcare corporations, they are drowned out at this conference by the advancing horde of finance guys in red ties and the CEOs that love them.

http://medcitynews.com/2016/01/the-definitive-guide-to-the-j-p-morgan-healthcare-conference/?rf=1

Signal Podcast on STAT

By LUKE TIMMERMANandMEG TIRRELL

JANUARY 7, 2016

Episode-5_Signal_SanFranConference_MollyFerguson-1024x576

MOLLY FERGUSON FOR STAT

How biotech went from a risky investment to a booming Business

http://www.statnews.com/2016/01/07/signal-podcast-birth-of-biotech/

Listen to Episode 5: By LUKE TIMMERMANandMEG TIRRELL

https://soundcloud.com/stat-signal-podcast/episode-5-san-francisco-in-january-is-where-new-medicines-get-made

San Francisco 2016

Union Square: Maps & Resources by MacDougall Biomedical Communications.

http://macb.io/jpm2016/

Biotech Showcase™ 2016 Program Overview

Sunday, January 10, 2016
1:00–5:00 pm
Additional Program
Biotech Showcase™ pre-event
The art and tactics of getting your fund raise done

This workshop is focused on delivering results and securing funding at All Levels: Boards, Angels, VCs, Corporate Partners and Other Sources of Funds, with four hours of intensive and interactive discussion, on-your-feet sessions, war stories and insights aimed at folks looking for financing. It is designed to accelerate your funding activities and eliminate unnecessary noise.

Preregistration is required, more information can be found here.
3:00–6:00 pm
Level 4, Cyril Magnin Foyer

All Biotech Showcase attendees are invited to pick up name badges prior to the beginning of the conference on Monday.

Monday, January 11, 2016
7:00 am
Level 4, Cyril Magnin Foyer
Registration Opens and Continental Breakfast
8:00–8:55 am
Workshops
[ + ]The age of virtual pharma: Challenges and solutions for investor directors and successful boards
[ + ]Alzheimer’s disease: Has the tide turned?
 8:00 am–6:00 pm
One-to-one Meetings ►

Hilton Union Square
333 O’Farrell Street
Level 2, Ballroom

8:00–9:50 am

Regenerative Medicine and Advanced Therapies State of the Industry Briefing
[ + ]Introduction and industry update
[ + ]The 2016 sector forecast: Upcoming clinical data events
[ + ]The promise of Regenerative Medicine and Advanced Therapies in oncology

8:00 am–12:00 pm

Company Presentations ►

Private Biotech
Public Biotech

12:00–1:30 pm

Lunch Plenary
[ + ]The great pricing debate: Navigating through an industry sea change

1:45–5:30 pm

Company Presentations ►

Private Biotech
Public Biotech

Tuesday, January 12, 2016
7:00 am
Level 4, Cyril Magnin Foyer
Registration Opens and Continental Breakfast
8:00–8:55 am
Workshops
[ + ]Corporate venture: Pharma’s eye on the early stage
[ + ]The Life Sciences Report 2016 small-cap watchlist
[ + ]London and the UK: A global hub for life sciences and investment
 8:00 am–6:00 pm
One-to-one Meetings ►

Hilton Union Square
333 O’Farrell Street
Level 2, Ballroom

8:00–9:15 am

Medtech Showcase State of the Industry Report
[ + ]Medtech Showcase State of the Industry Report

8:00 am–12:00 pm

Company Presentations ►

Private Biotech
Public Biotech

12:00–1:30 pm

Lunch Plenary
[ + ]State of the industry: It’s different this time

1:45–5:30 pm

Company Presentations ►

Private Biotech
Public Biotech

4:30–5:30 pm

Medtech Showcase Workshop
[ + ]Advanced medical technology: What investors need to know

 

Wednesday, January 13, 2016
7:00 am
Level 4, Cyril Magnin Foyer
Registration Opens and Continental Breakfast
8:00–8:55 am

Workshops
[ + ]FDA 2016: New FDA Commissioner, PDUFA reauthorization process and biomarkers
[ + ]Investing in the immuno-oncology revolution: Follow the T cells
 8:00 am–5:00 pm
One-to-one Meetings ►

Hilton Union Square
333 O’Farrell Street
Level 2, Ballroom

8:00–9:00 am

Digital Health Showcase State of the Industry Report
[ + ]At the intersection of technology and medicine

8:00 am–12:00 pm

Company Presentations ►

Private Biotech
Public Biotech

10:00–11:00 am

Digital Health Showcase Workshop
[ + ]Who’s investing in digital medicine?

11:00–11:45 am

[ + ]Fireside chat

11:45 am–12:15 pm

Digital Health Showcase Discussion
[ + ]Top 10 digital health trends: Implications for early to mid-stage biopharma

12:00–1:30 pm

Lunch Plenary
[ + ]Bubble trouble? Have the biotech bulls had their run?

1:00–1:45 pm

Digital Health Showcase Workshop
[ + ]The regulatory pathway: Is it getting clearer?

4:00–5:00 pm

Digital Health Showcase Workshop
[ + ]A look at big pharma’s interest in digital medicine

1:45–5:00 pm

Company Presentations ►

Private Biotech
Public Biotech

5:00–6:00 pm

Level 4, Cyril Magnin Foyer
Closing Reception

 

SOURCE

http://www.ebdgroup.com/bts/program/index.php

About Biotech Showcase™ 2016

Previous conferences ►

Biotech Showcase™ 2016
January 11–13, 2016, San Francisco

Biotech Showcase™ 2015 Highlights

  • 232 company presentations
  • 2,100 attendees
  • 1,276 companies
  • 37 countries represented
  • 4,277 one-to-one meetings
  • 14 workshops and panels

Photos of Biotech Showcase 2015 ►

Biotech Showcase™ is an investor and networking conference devoted to providing private and public biotechnology and life sciences companies with an opportunity to present to, and meet with, investors and potential strategics in one place during the course of one of the industry’s largest annual healthcare investor conferences. Investors and biopharmaceutical executives from around the world gather in San Francisco during this critical week which is widely viewed as setting the tone for the coming year.

Now in its eighth year, this rapidly growing conference features multiple tracks of presenting companies, plenary sessions, workshops, networking, and an opportunity to schedule one-to-one meetings.

Biotech Showcase delegates include investors in private and public companies, sector analysts, bankers and industry professionals, as well as biopharmaceutical and life science company executives.

Biotech Showcase is produced by Demy Colton Life Science Advisors and EBD Group. Both organizations have a long history of producing high quality programs that support the biotechnology and broader life sciences industry.

http://www.ebdgroup.com/bts/media/about_conf.php

Biotech Showcase™ 2016 Press Releases

J.P. Morgan 34th Annual Healthcare Conference

When:

January 11, 2016 – January 14, 2016 (all-day)

Where:

San Francisco, CA, USA

Conference AGENDA

http://jpmorgan.metameetings.com/confbook/healthcare16/agenda.php 

 

J.P. MORGAN HEALTHCARE CONFERENCE 2016 SURVIVAL GUIDE

 

Whether you’re a conference veteran or a rookie, we hope this light-hearted guide helps you survive the week of life science mayhem in San Fransisco. At Chempetitive Group, we have a deep passion for everything life science—its people, its processes and its promise for the future. As life science marketers, this passion takes us to the industry’s biggest events every year, including the J.P. Morgan Healthcare Conference and related conferences each January. Over the years, we’ve learned our way around San Francisco’s Union Square—places we like to frequent.

 

January 11-14 San Francisco RAMP UP

Over 12,000 attendees

Over 15,000 meetings

Over 1,500 companies presenting

http://www.ebdgroup.com/bts/presenters/prs_comps.php

Over 40 countries represented Projected value of this year’s deals: unlimited

Surviving the J.P. Morgan Healthcare Conference [Plus Insider’s Guide]

POSTED BY:
ERIK CLAUSEN

Each January, the J.P. Morgan Healthcare Conference – perhaps the life science industry’s largest and most frenzied conference of the year – reliably draws thousands of investors and executives across the healthcare sector to San Francisco’s Union Square neighborhood as hundreds of companies present their latest innovations and dreams in an attempt to pique the interest of venture capitalists and potential partners. In addition to J.P. Morgan, parallel events Biotech Showcase, OneMedForum and RESI Conference ensure that there is a high density of biotech brainpower and capital in the City by the Bay.

The conference week is a mix of long days of presentations and lively evenings of cocktail parties and networking events. With more than 50 networking receptions, days of sessions, and still a volume of work to manage while away from the office, you might need some guidance on where to take your client or potential partner for a meeting, where to refuel or caffeinate, or simply where to hide from the chaos. For these reasons, we decided to let you into our world by creating this simple guide to surviving the 2016 J.P. Morgan Healthcare Conference week.

Download it and, if you happen to find yourself in one of our favorite spots, let us know with a direct message on Twitter at @chempetitive. Safe travels, have fun, and get some deals done.

JP Morgan 2016 Healthcare Conference Participants

The following organizations have released announcements of their participation in the 34th Annual JP Morgan Healthcare Conference:

http://globalbiodefense.com/2015/12/28/jp_morgan_healthcare_2016/#sthash.IhPw1DcA.dpuf

SOURCE

http://chempetitive.com/chemunity/jp-morgan-healthcare-conference-san-francisco-2016

http://info.chempetitive.com/hubfs/jp-morgan-infographic.pdf?__hssc=206009548.1.1452199074195&__hstc=206009548.1433c7a0bae9903565d9225ff3a2e21a.1452199074194.1452199074194.1452199074194.1&hsCtaTracking=4f124550-2dd0-4834-b2e3-1bcf78ce32bc%7C8020c5d5-e8f4-4e7e-95df-a299dd5dffbc

 

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Two New Drugs for Inflammatory Bowel Syndrome Are Giving Patients Hope

Posted in Immunology, Immunotherapy, Inflammasome, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, tagged , , , , , , , , , , , on January 7, 2016| Leave a Comment »

 

Two New Drugs for Inflammatory Bowel Syndrome Are Giving Patients Hope

Reporter: Stephen J. Williams, Ph.D.

Actavis Receives FDA Approval for VIBERZI (eluxadoline) for the Treatment of Irritable Bowel Syndrome with Diarrhea (IBS-D) in Adults -First in class treatment for IBS-D treats hallmark symptoms of IBS-D; abdominal pain and diarrhea

DUBLIN, May 27, 2015 /PRNewswire/ — Actavis plc (NYSE: ACT) announced today that VIBERZI™ (eluxadoline) was approved by the Food and Drug Administration (FDA) as a twice-daily, oral treatment for adults suffering from irritable bowel syndrome with diarrhea (IBS-D). VIBERZI (eluxadoline) has mixed opioid receptor activity, it is a mu receptor agonist, a delta receptor antagonist, and a kappa receptor agonist.

Logo – http://photos.prnewswire.com/prnh/20130124/NY47381LOGO

“The FDA’s approval of VIBERZI is the first step to providing physicians with a new, evidence-based, treatment option for their adult patients with IBS-D,” said David Nicholson, Executive Vice President, Actavis Global Brands R&D. “At Actavis, we are dedicated to providing new treatment options, and the development of new agents that help address the most bothersome symptoms of IBS-D. We are very pleased to be working with the FDA to advance this IBS-D treatment and we eagerly await DEA scheduling determination later this year.”

IBS-D is a multifactorial disorder marked by recurrent abdominal pain or discomfort and altered bowel function that affects as many as 15 million adult Americans, impacting about twice as many women as men.i,ii,iii There are few treatment options available for IBS-D, particularly options that relieve both the diarrhea and abdominal pain associated with IBS-D.

“The unpredictable symptoms experienced by patients with IBS-D can have a significant impact on everyday life,” said William D. Chey, MD, Nostrant Professor of Gastroenterology at the University of Michigan Health System. “It’s exciting when physicians are able to add an additional treatment option like VIBERZI to their toolbox for patients with IBS-D.”

The FDA has recommended that VIBERZI be classified as a controlled substance. This recommendation has been submitted to the U.S. Drug Enforcement Administration (DEA).  Once VIBERZI receives final scheduling designation, the updated label will be available. Pending final scheduling designation, product launch is anticipated in Q1 2016.

About VIBERZI

VIBERZI is an orally active compound indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in men and women. VIBERZI (eluxadoline) has mixed opioid receptor activity, it is a mu receptor agonist, a delta receptor antagonist, and a kappa receptor agonist.

Efficacy was established in two Phase III clinical studies, demonstrating significant superiority over placebo on the composite endpoint of simultaneous improvement in both abdominal pain and diarrhea at both 75 mg and 100 mg twice daily doses. The primary efficacy responder endpoint was evaluated over the duration of double-blind, placebo-controlled treatment. Response rates were compared based on patients who met the daily composite response criteria (improvement in both abdominal pain and stool consistency on the same day) for at least 50% of the days from weeks 1 to 12 (FDA endpoint) and weeks 1 to 26 (European Medicines Agency endpoint).

The most common adverse events in the two Phase III clinical trials were constipation (7% and 8% for eluxadoline 75 mg and 100 mg; 2% for placebo) and nausea (8% and 7% for eluxadoline 75 mg and 100 mg; 5% for placebo). Rates of severe constipation were less than 1% in patients receiving 75 mg and 100 mg eluxadoline. Rates of discontinuation due to constipation were low for both eluxadoline and placebo (≤2%) and similar rates of constipation occurred between the active and placebo arms beyond 3 months of treatment. A total of 2,426 subjects were enrolled across the two studies.

For more information including full prescribing information about VIBERZI at http://www.actavis.com/Actavis/media/PDFDocuments/VIBERZI_PI.pdf

About IBS-D

Irritable bowel syndrome with diarrhea (IBS-D) is a functional bowel disorder characterized by chronic abdominal pain and frequent diarrhea, which affects approximately 15 million patients in the U.S.  Although the exact cause of IBS-D is not known, symptoms are thought to result from a disturbance in the way the gastrointestinal tract and nervous system interact.

IBS-D can be debilitating and there are limited therapeutic options for managing the chronic symptoms. IBS-D is associated with economic burden in direct medical costs and indirect social costs such as absenteeism and lost productivity, along with decreased quality of life.

About Actavis
Actavis plc (NYSE: ACT), headquartered in Dublin, Ireland, is a unique, global pharmaceutical company and a leader in a new industry model—Growth Pharma. Actavis is focused on developing, manufacturing and commercializing innovative branded pharmaceuticals, high-quality generic and over-the-counter medicines and biologic products for patients around the world.

Actavis markets a portfolio of best-in-class products that provide valuable treatments for the central nervous system, eye care, medical aesthetics, gastroenterology, women’s health, urology, cardiovascular and anti-infective therapeutic categories, and operates the world’s third-largest global generics business, providing patients around the globe with increased access to affordable, high-quality medicines. Actavis is an industry leader in research and development, with one of the broadest development pipelines in the pharmaceutical industry and a leading position in the submission of generic product applications globally.

With commercial operations in approximately 100 countries, Actavis is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives.

Actavis intends to adopt a new global name – Allergan – pending shareholder approval in 2015.

For more information, visit Actavis’ website at www.actavis.com.

Actavis Cautionary Statement Regarding Forward-Looking Statements

Statements contained in this communication that refer to Actavis’ estimated or anticipated future results, including estimated synergies, or other non-historical facts are forward-looking statements that reflect Actavis’ current perspective of existing trends and information as of the date of this communication. Actual results may differ materially from Actavis’ current expectations depending upon a number of factors affecting Actavis’ business. These factors include, among others, the timing and success of product launches; the difficulty of predicting the timing or outcome of product development efforts and regulatory agency approvals or actions, if any; market acceptance of and continued demand for Actavis’ products; difficulties or delays in manufacturing; and such other risks and uncertainties detailed in Actavis’ periodic public filings with the Securities and Exchange Commission, including but not limited to Actavis plc’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2015 and from time to time in Actavis’ other investor communications. Except as expressly required by law, Actavis disclaims any intent or obligation to update or revise these forward-looking statements.

i Camilleri M. Current and future pharmacological treatments for diarrhea-predominant irritable bowel syndrome. Expert Opinion on Pharmacotherapy. 2013;14:1151.

ii Grundmann O, Yoon SL. Irritable bowel syndrome: epidemiology, diagnosis, and treatment: an update for health-care practitioners. Journal of Gastroenterology and Hepatology. 2010;25:691–699.

iii Eluxadoline Xifaxin Summary Final. November 2014.

CONTACTS:
Investors:
Lisa DeFrancesco
(862) 261-7152

Media:
David Belian
(862) 261-8141

SOURCE Actavis plc

RELATED LINKS
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Synergy’s Looming FDA Filing Makes It Pharma of the Month

By James Passeri Follow

| Jan 05, 2016 | 8:39 AM EST  | 0

Keep an eye on Synergy Pharmaceuticals (SGYP) this month: Analysts like it, its shares have waned since a big spike this summer, and the official filing of its star product is expected any day.

When the New York-based pharmaceutical company, which specializes in gastrointestinal therapy, announced that it passed clinical trials on its flagship drug plecanatide this summer, shares rocketed 95%.

But today analysts appear mystified at why the stock has receded 45% from its July high, especially with plecanatide’s new drug application with the Food and Drug Administration expected this month. (It’s currently trading below $6, and the consensus price target is over $13, according to data provided by Bloomberg.)

Synergy should be raking in $600 million from plecanatide, a daily tablet that treats patients with irritable bowel syndrome (IBS), within five years of obtaining FDA approval (expected in 2017, according to equity research firm BTIG. Synergy currently has a market capitalization of just $645 million.

BTIG’s $11 price target is also buoyed by roughly $142 million on the balance sheet, as well as newly appointed management including CFO Gary Sender and COO Troy Hamilton, both former executives at pharma success story Shire (SHPG). Though Shire shares are down just under 4% over the past 12 month, they have rocketed 112% over the past two years.

Synergy also stands to benefit from a growing demand for gastrointestinal treatments, feeding the appetite of Big Pharma for potential acquisitions, according to BTIG.

“With about 45 million Americans suffering from chronic constipation and IBS, and major companies like Allergan(AGN) and Valeant (VRX) focusing their marketing efforts on GI treatments, it seems logical to imagine SGYP as a takeover candidate,” BTIG analyst Timothy Chiang wrote in a November report.

Whether or not this leads to a buyout or another stock surge, Synergy certainly can be counted on for a healthy dose of small-cap volatility as its chief product takes the final steps toward reaching its customers.

 

 

Synergy Pharmaceuticals Announces Successful End-of-Phase 2 Meeting with FDA for Plecanatide in Irritable Bowel Syndrome with Constipation

Download PDF

Pivotal Phase 3 IBS-C Program to be Initiated in the Fourth Quarter of 2014

NEW YORK– Synergy Pharmaceuticals Inc. (NASDAQ:SGYP) today announced that it has successfully completed an End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) on its lead drug plecanatide for the treatment of irritable bowel syndrome with constipation (IBS-C). Agreement was reached with the FDA for the plecanatide pivotal phase 3 IBS-C clinical development program that is scheduled to begin in the fourth quarter of this year.

“We are very pleased with the outcome of our meeting with the FDA and have a clear path forward to start the IBS-C registration program with plecanatide this year,” said Dr. Gary S. Jacob, Chairman and CEO of Synergy. “The pivotal phase 3 IBS-C trials will include both 3.0 mg and 6.0 mg plecanatide, which are consistent with the doses currently being evaluated in our phase 3 chronic idiopathic constipation (CIC) program. Plecanatide has demonstrated a clinical dose-response for efficacy with an excellent tolerability profile that is observed across trials. This is an important advantage as we look to bring two doses to market in both indications and provide physicians with options for addressing individual patient needs.”

Synergy’s pivotal phase 3 IBS-C clinical development program will consist of two registration trials, each including 1,050 patients who will receive either placebo, 3.0 mg or 6.0 mg plecanatide. IBS-C patients successfully completing either of the 12-week placebo-controlled registration trials will be offered enrollment into a long-term safety trial in order to complement and support the ongoing long-term safety database for the CIC indication.

About Plecanatide

Plecanatide is Synergy’s lead uroguanylin analog in late-stage clinical development to treat patients with CIC and IBS-C. Uroguanylin is a natural gastrointestinal (GI) hormone produced by humans in the small intestine and plays a key role in regulating the normal functioning of the digestive tract through its activity on the guanylate cyclase-C (GC-C) receptor. The GC-C receptor is known to be a primary source for stimulating a variety of beneficial physiological responses. Orally administered plecanatide mimics uroguanylin’s functions by binding to and activating the GC-C receptor to stimulate fluid and ion transit required for normal bowel function. Synergy has successfully completed a phase 2b trial of plecanatide in 951 patients with CIC and is currently enrolling patients in two pivotal phase 3 CIC trials. The company also recently announced positive top-line data results from a phase 2b dose-ranging study with plecanatide in patients with IBS-C.

About Synergy Pharmaceuticals

Synergy Pharmaceuticals (NASDAQ:SGYP) is a biopharmaceutical company focused on the development of novel therapies based on the natural human hormone, uroguanylin, to treat GI diseases and disorders. Synergy has created two unique analogs of uroguanylin – plecanatide and SP-333 – designed to mimic the natural hormone’s activity on the GC-C receptor and target a variety of GI conditions. SP-333 is currently in phase 2 development for opioid-induced constipation and is also being explored for ulcerative colitis. For more information, please visit www.synergypharma.com.

 

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Genomics’ Proprietary Statistical Analysis Tools and Integrated Multi-Phenotype Database to be used to Support Research and Development at Vertex Pharmaceuticals

Posted in Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical R&D Informatics, Pharmacogenomics on January 4, 2016| Leave a Comment »

Genomics’ Proprietary Statistical Analysis Tools and Integrated Multi-Phenotype Database to be used to Support Research and Development at Vertex Pharmaceuticals, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Genomics’ Proprietary Statistical Analysis Tools and Integrated Multi-Phenotype Database to be used to Support Research and Development at Vertex Pharmaceuticals

Reporter: Aviva Lev-Ari, PhD, RN

 

 

Press release

04 January 2016

Genomics and Vertex Collaborate to Identify Target Therapeutic Pathways

 

Genomics’ Proprietary Statistical Analysis Tools and Integrated Multi-Phenotype Database to be used to Support Research and Development at Vertex Pharmaceuticals

 

Oxford, UK, 04 January 2016: Genomics plc (“Genomics”), a leading analysis company developing algorithms, data resources, and software solutions to uncover the relationships between genetic variation and human disease, today announced that Vertex Pharmaceuticals will use Genomics’ integrated database and state-of-the-art analysis tools to inform its drug research and development.  These tools aim to provide confidence in the rationale for targeting Vertex’s pathways of interest for the treatment of certain diseases and to identify potential safety concerns and repositioning opportunities.

 

Genomics has developed a unique analytical platform for genome analysis and interpretation. The platform combines proprietary algorithms and software with the Company’s integrated genome-phenome database and analytical expertise to learn about human biology.  Genomics has several existing partnerships with large pharmaceutical companies, and in clinical genomics is a Platform Partner for Genomics England, the company undertaking the 100,000 Genomes Project in the UK.

 

John Colenutt, CEO, Genomics plc, said: “Pharmaceutical and biotech companies are increasingly using human genetic data in research to increase the chance of success in drug development.  We are excited that Vertex has chosen to use Genomics’ proprietary technology, integrated database and tools to support them in this aim.”

 

Paul de Bakker, Ph.D., Head of Computational Genomics for Vertex said: “Vertex is focused on advancing research programs where disease mechanisms are validated by human biology.  Our collaboration with Genomics is aimed at obtaining insights into the genetic underpinnings of specific targets and diseases to help predict which potential medicines may have success moving from discovery research toward patients.”

 

ENDS

 

Photo: John Colenutt, CEO, Genomics plc. For a high resolution image please contact lorna.cuddon@zymecommunications.com

 

For further information please contact:

 

Zyme Communications

Lorna Cuddon

Tel: +44 (0)7811996942

Email: lorna.cuddon@zymecommunications.com

 

About Genomics plc http://www.genomicsplc.com/

Genomics was founded by four leading Oxford academics, including Professor Peter Donnelly, Director of The Wellcome Trust Centre for Human Genetics, and Professor Gil McVean, Director of The Big Data Institute. The Company has developed a unique platform for genomic sequence data analysis and interpretation which combines world-leading expertise in statistical analysis and data mining with a unique integrated database linking genotypes and phenotypes. Genomics England, the company running the UK project to undertake whole genome sequencing of 100,000 patients in the National Health Service, has appointed Genomics plc as a Platform Partner and has also awarded the Company three SBRI grants. Genomics plc is also working with four major pharmaceutical companies to bring the benefits of genomic analysis to their drug development processes. The Company is supported by major investors, including IP Group, Invesco Perpetual, Woodford Investment Management and Lansdowne Partners.

SOURCE

From: Lorna Cuddon <lorna.cuddon@zymecommunications.com>

Reply-To: <lorna.cuddon@zymecommunications.com>

Date: Monday, January 4, 2016 at 4:11 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Genomics and Vertex Collaborate to Identify Target Therapeutic Pathways

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Top Seven Big Pharma in Thomson Reuters 2015 Top 100 Global Innovators

Posted in Intellectual Property, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, Patents, Pharmaceutical Analytics, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Informatics, Pharmaceutical R&D Investment on January 4, 2016| Leave a Comment »

Top Seven big Pharma in Thomson Reuters 2015 Top 100 Global Innovators

Reporter: Aviva Lev-Ari, PhD, RN

 

NAME COUNTRY PREVIOUS WINNER PREVIOUS WINNER PREVIOUS WINNER
Abbott USA

2014

 2013
Bayer GERMANY

2011
Boehringer

Ingelheim

 GERMANY
Brinstol-Myers Squibb USA

2011
J&J USA

2014

2013
Novartis Switzerland

2014
Roche Switzerland

2014

 2013

2012, 2011

SOURCE

http://images.info.science.thomsonreuters.biz/Web/ThomsonReutersScience/%7Beb621c66-e238-4994-b1b5-9f5f9f897a75%7D_Thomson_Reuters_Top100_Global_Innovators_final.pdf

Introducing the Thomson Reuters 2015 Top 100 Global Innovators Organization Country Industry Previous Winners

New in 2015:

Top Bay Area Innovators For the first time, Thomson Reuters analysts studied Silicon Valley, known as the technology and innovation corridor in the US, to see which companies are leading there. Following a methodology similar to that of the Top 100 Global Innovators, except for the Volume criteria, all companies headquartered or with a major subsidiary in that region were investigated. The Top Bay Area Innovators list can be found on page 19. There are 11 companies that overlap with the Top 100 Global Innovators; meaning 31 percent of the leading US innovators and 11 percent of the world’s top innovators are located in the Bay Area.

Absentees:

The United Kingdom is absent from the list yet again this year. Innovation incentives introduced in the UK, such as Patent Box legislation, do not have enough legacy yet to have had an impact. Additionally, the UK spends much less on R&D as a percentage of Gross Domestic Product (GERD) than the Top 100 Global Innovator countries do. The UK’s GERDis 1.63 percent, whereas, for example, Japan’s is 3.47 percent.5 The region’s underuse of its patent system and lack of significant commercialization keep the UK from making the list once again.

China is also absent from the 2015 list. It joined the innovation-leader ranks in 2014, for the first time, via Huawei, however wasn’t able to replicate that performance to join again in 2015. A big factor contributing to China’s shortcoming is the fact that most of its innovation is domestic and therefore is not realized outside of its borders. In fact, only about six percent of China’s innovation activity is protected, and commercialized, outside of China. In order for China to see more organizations join this prestigious group, it will need to think more internationally and look to bring its inventions to market around the world. There are 27 companies that dropped from the prior year (see Table 1 on page 12), including AT&T, IBM, Siemens and Xerox. While these companies are still innovating at noteworthy levels, their respective scores across all of the metrics did not advance them to the Top 100. It’s expected that we will see them again in the future.

Patent Reform

There’s been some influential intellectual property legislation that is shaping how companies innovate, where they seek protection and when. Some of these initiatives include the America Invents Act and the Patent Trial & Appeal Board; the European unitary patent and unified patent court; the UK’s Patent Box legislation; and impactful court rulings, such as Alice 101 in the US. The landscape is ripe with reform as patent offices and filers grapple with how best to implement these changes given their goals and needs. Despite these changes, one thing remains certain: the patent system is vital to protecting innovation and to the economic wellbeing of organizations, nations and our world. OECD statistics confirm that nations with higher GDPs have similarly high patent filing rates (aka strong patent infrastructures), whereas the converse holds equally true. One way for developing nations to propel their economies forward is to invest in innovation and building a reliable intellectual property infrastructure.

Methodology

The Thomson Reuters Top 100 Global Innovator methodology analyzes patent and citation data across four main criteria:

  • volume,
  • success,
  • globalization and
  • influence

using Thomson Reuters solutions including Derwent World Patents Index (DWPI), Thomson Innovation and Derwent Patent Citations Index (PCI).

Volume

Volume is the first criteria. An organization must have at least 100 unique inventions protected by a granted patent over the most recent five year period to advance for further analysis. A unique invention is defined as one instance of a published application or granted patent for an idea for which protection is sought. In DWPI, these are called “basic” patents. DWPI provides access to 50 patentissuing authorities. Subsequent filings for the same invention are recorded as equivalents and collated into patent families which, for this analysis, were not included. Once an organization passes the volume stage gate, it is measured across the next three criteria: success, globalization and influence.

Success

The success metric covers the ratio of inventions described in published applications (those patents which are filed and publicly published by the patent office but not yet granted) to inventions protected with granted patents over the most recent five years. Not all patent applications pass through the examination process and are granted.

Globalization

Globalization has to do with the value an organization places on an invention by protecting it across the major world markets. The premise being that inventions protected in all four of the Thomson Reuters Quadrilateral Patent Index authorities: the Chinese Patent Office, the European Patent Office, the Japanese Patent Office and the United States Patent & Trademark Office, are deemed to be of significant value to the organization. A ratio is created of the inventions protected across the Quadrilateral Patent Index authorities versus the total volume for that period. Influence Finally,

Influence

influence is the downstream impact of an invention, measured by how often it is cited by other organizations. Via the Derwent Patent Citation Index, citations to an organization’s patents are counted over the most recent five years, excluding self citations. Scores for each of these areas are tallied and combined to produce the Top 100 Global Innovator list.

Top 100 Global Innovator list

3M Company USA Chemical 2011, 2012, 2013, 2014

Abbott Laboratories USA Pharmaceutical 2013, 2014

Advanced Micro Devices USA Semiconductor & Electronic Components 2011, 2012, 2013, 2014

Air Products USA Chemical 2013

Aisin Seiki Japan Automotive 2014

Alcatel-Lucent France Telecommunication & Equipment 2011, 2012, 2013, 2014

Alstom France Electrical Power

Amazon USA Media Internet Search & Navigation Systems

Analog Devices USA Semiconductor & Electronic Components 2011, 2012, 2013

Apple USA Telecommunication & Equipment 2011, 2012, 2013, 2014

Arkema France Chemical 2011, 2012, 2013, 2014

Avago Technologies (previously LSI) USA Semiconductor & Electronic Components 2011,2012, 2013, 2014

BASF Germany Chemical 2011, 2014

Bayer Germany Pharmaceutical 2011

Becton Dickinson USA Medical Devices

Blackberry Canada Telecommunication & Equipment 2013, 2014

Boehringer Ingelheim Germany Pharmaceutical

Boeing USA Aerospace 2011, 2012, 2013, 2014

Bridgestone Japan Automotive

Bristol-Myers Squibb USA Pharmaceutical 2011

Canon Japan Imaging 2011, 2012, 2013, 2014

Casio Computer Japan Computer Hardware 2014

Chevron USA Oil & Gas 2011, 2012, 2013

CNRS, The French National Center for Scientific Research France Scientific Research 2011, 2012, 2013, 2014

CEA–The French Alternative Energies and Atomic Energy Commission France Scientific Research 2011, 2012, 2013, 2014

Daikin Industries Japan Industrial 2011, 2014

Dow Chemical Company USA Chemical 2011, 2012, 2013, 2014

DuPont USA Chemical 2011, 2012, 2013, 2014

Emerson Electric USA Electrical Products 2012, 2013, 2014

Ericsson Sweden Telecommunication & Equipment 2011, 2012, 2013, 2014

Exxon Mobil USA Oil & Gas 2011, 2012, 2013

Fraunhofer Germany Scientific Research 2013, 2014

Freescale Semiconductor USA Semiconductor & Electronic Components 2013, 2014

Fujifilm Japan Imaging 2012, 2013, 2014

Fujitsu Japan Computer Hardware 2011, 2012, 2013, 2014

Furukawa Electric Japan Electrical Products 2014

General Electric USA Consumer Products 2011, 2012, 2013, 2014

Google (now Alphabet Inc.) USA Media Internet Search & Navigation Systems 2012, 2013, 2014

Hitachi Japan Computer Hardware 2011, 2012, 2013, 2014

Honda Motor Japan Automotive 2011, 2012, 2013, 2014

Honeywell International USA Electrical Products 2011, 2012, 2013, 2014

Idemitsu Kosan Japan Oil & Gas

IFP Energies Nouvelles France Scientific Research 2011, 2012, 2013, 2014

Intel USA Semiconductor & Electronic Components 2011, 2012, 2013, 2014

InterDigital USA Telecommunication & Equipment

Japan Science and Technology Agency (JST) Japan Scientific Research

Johnson & Johnson USA Pharmaceutical 2013, 2014

Johnson Controls USA Automotive

JTEKT Japan Automotive Kawasaki Heavy Industries Japan Industrial

Kobe Steel Japan Primary Metals 2014

Komatsu Japan Industrial 2014

Kyocera Japan Electrical Products 2014

LG Electronics S Korea Consumer Products 2011, 2012, 2013, 2014

Lockheed Martin USA Transportation Equipment 2012, 2013, 2014

LSIS S Korea Electrical Power 2011, 2012, 2013, 2014

Makita Corporation Japan Machinery

Marvell USA Semiconductor & Electronic Components 2012, 2013, 2014

MediaTek Taiwan Semiconductor & Electronic Components 2014

Medtronic USA Medical Devices 2014

Micron USA Semiconductor & Electronic Components 2012, 2013, 2014

Microsoft USA Computer Software 2011, 2012, 2013, 2014

Mitsubishi Electric Japan Electrical Products 2011, 2012, 2013, 2014

Mitsubishi Heavy Industries Japan Machinery 2012, 2013, 2014

Mitsui Chemicals Japan Chemical NEC Japan Computer Hardware 2011, 2012, 2013, 2014

Nike USA Consumer Products 2012, 2013, 2014

Nippon Steel & Sumitomo Metal Japan Primary Metals 2012, 2013, 2014

Nissan Motor Japan Automotive 2013, 2014

Nitto Denko Japan Chemical 2011, 2012, 2013, 2014

Novartis Switzerland Pharmaceutical 2014 2015

NTT Japan Telecommunication & Equipment 2011, 2012, 2013, 2014

Olympus Japan Healthcare Products 2011, 2012, 2013, 2014

Oracle USA Computer Software 2013, 2014

Panasonic Japan Consumer Products 2011, 2012, 2013, 2014

Philips Netherlands Electrical Products 2011, 2013, 2014

Qualcomm USA Semiconductor & Electronic Components 2011, 2012, 2013, 2014

Roche Switzerland Pharmaceutical 2011,2012,2013, 2014

Safran France Transportation Equipment 2013, 2014

Saint-Gobain France Industrial 2011, 2012, 2013, 2014

Samsung Electronics S Korea Semiconductor & Electronic Components 2011, 2012, 2013, 2014

Seagate USA Computer Hardware 2012, 2013, 2014

Seiko Epson Japan Imaging 2011, 2012, 2013, 2014

Shin-Etsu Chemical Japan Chemical 2011, 2012, 2013, 2014

Showa Denko Japan Chemical

Solvay Belgium Chemical 2012

Sony Japan Consumer Products 2011, 2012, 2013, 2014

Sumitomo Electric Japan Industrial 2011, 2013, 2014

Symantec USA Computer Software 2011, 2012, 2013, 2014

TE Connectivity Switzerland Semiconductor & Electronic Components 2011, 2012, 2013, 2014

Thales France Transportation Equipment 2012, 2013

Toray Japan Chemical

Toshiba Japan Computer Hardware 2011, 2012, 2013, 2014

Toyota Motor Japan Automotive 2011, 2012, 2013, 2014

Valeo France Automotive 2012, 2013

Xilinx USA Semiconductor & Electronic Components 2012, 2013, 2014

Yamaha Japan Consumer Products 2011, 2014

Yamaha Motor Japan Automotive

Yaskawa Electric Japan Industrial

Yazaki Japan Automotive

 

SOURCE

http://images.info.science.thomsonreuters.biz/Web/ThomsonReutersScience/%7Beb621c66-e238-4994-b1b5-9f5f9f897a75%7D_Thomson_Reuters_Top100_Global_Innovators_final.pdf

 

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