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Phosphodiesterase Targets for Cognitive Dysfunction and Schizophrenia
Tuesday, January 26, 2010
Cyclic nucleotide signaling pathways are critical regulators of neural function and plasticity. Alterations in these pathways have been implicated in various disorders of the brain, including depression, schizophrenia and cognitive disorders. Intra-cellular signaling of dopamine D1 and various serotonin receptors, which signal through cyclic nucleotides, is known to be defective in these disorders. Phosphodiesterases, (PDEs) by virtue of the metabolic inactivation of cAMP and cGMP, are key regulators of cyclic nucleotide signaling pathways. PDEs are well accepted as “drugable” targets and PDE inhibitors are effective pharmaceutical agents. However, only recently have PDE systems been studied in the context of disorders of the brain. Currently there are concerted efforts to develop phosphodiesterase inhibitors as therapeutic agents for cognition and schizophrenia. Of the 11 families of PDEs, PDE4, PDE9 and PDE10 are actively being explored in human clinical testing. Other PDEs currently being investigated including PDE1B and PDE2 in the context of cognition. The symposium will bring together experts who are developing PDE inhibitors for schizophrenia and cognitive disorders, review the theoretical basis of different PDEs, and chart the most recent progress towards human clinical testing.
Agenda
8:30 AM | Registration and Continental Breakfast |
9:00 AM | Introduction |
9:10 AM | PDE Regulation of Cyclic Nucleotide Function: Roles of PDE8s |
9:55 AM | PDE1 Inhibitors for Cognitive Dysfunction in Schizophrenia |
10:40 AM | Refreshments |
11:00 AM | PDE10A for Schizophrenia: Cell Biology to Drug Discovery |
11:45 AM | Comparison of PDE9 and PDE10 Inhibitors in Preclinical |
12:30 PM | Lunch |
1:30 PM | Overview of Cognition in Schizophrenia |
| 2:15 PM | PDE Inhibitors and Cognitive Function: What We can Learn about |
3:00 PM | Refreshments |
3:20 PM | cAMP Signaling in Mouse Models of Psychiatric Disorders |
4:05 PM | PDE4 Isoenzymes in Memory |
4:50 PM | Closing Remarks |
5:00 PM | End of Symposium |
Speakers
Organizers
Lawrence P. Wennogle
Intra-Cellular Therapies, Inc.
Dr. Wennogle received his Ph.D. in Biochemistry from the University of Colorado, Boulder working under Drs. Howard Berg and Marvin Caruthers where he studied the structure of red blood cell membranes. He then completed two post-doctoral positions, one at the University of Colorado and the second at the Pasteur Institute in Paris, France, working under Jean-Pierre Changeux on the structure-function of the nicotinic acetylcholine receptor for Torpedo mamorata. For the past 29 years, Dr. Wennogle has been involved in the research and development in the pharmaceutical industry aimed at discovery of novel pharmaceutical entities for human diseases. He was a Staff Scientist and Principal Research Fellow at Ciba-Geigy and Novartis for 19 years, where he led drug discovery programs for CNS disorders, cardiovascular disease, diabetes and inflammation. Included in his experiences while at Novartis, he served on an “Expert Committee in Molecular Biology” with world-wide responsibility to evaluate new technologies. With his broad expertise in drug discovery and the biochemical basis of disease, Dr. Wennogle supervises Intra-Cellular Therapies (ITI) development of small molecule therapeutics for neurodegenerative and neuropsychiatric disorders. ITI currently has a clinical candidate for schizophrenia in phase 2 clinical trials. Dr. Wennogle is a Fellow of the New York Academy of Sciences and has co-authored over 45 scientific publications. He is a member of the New York Academy of Sciences, the American Association for the Advancement of Science, and the Society for Neurosciences. He has adjunct appointments at Columbia University in the Department of Pharmacology and at University of Medicine and Dentistry, New Jersey in the Graduate School of Biomedical Sciences. His current focus is the development of novel therapeutics for cognitive dysfunction.
Peter Hutson
Merck and Co., Inc.
Dr Pete Hutson received his PhD in pharmacology from the Institute of Neurology, University of London where he studied the role of stress and 5-HT1A presynaptic autoreceptors on the regulation of brain serotonin function. He subsequently joined the Neuroscience Research Centre, Merck Sharp and Dohme in the UK and led drug development and research programs for CNS disorders. He is a member of the Society for Neuroscience and European College of Neuropsychopharmacology and has co-authored over 50 scientific publications. Dr Pete Hutson is currently the head of the Psychiatry Research department, Merck and Co. Inc., West Point, USA and is currently focused on the development of novel therapeutics for schizophrenia and depression.
Speakers
Ted Abel
University of Pennsylvania
Dr. Ted Abel is the Edmund J. and Louise W. Kahn Term Professor of Biology and Director of the Biological Basis of Behavior Program at the University of Pennsylvania. He also directs an NIMH Graduate Training Program in Behavioral and Cognitive Neuroscience at Penn. Dr. Abel was an undergraduate at Swarthmore College, receiving a B.A. in Chemistry in 1985. After Swarthmore, Dr. Abel attended the University of Cambridge (Christ’s College) as a Marshall Scholar, receiving an M. Phil. in Biochemistry and working with Dr. R. Tim Hunt on the cloning of cyclin. Dr. Abel then moved to Harvard University to work with Dr. Tom Maniatis on transcriptional regulation during Drosophila development as a National Science Foundation graduate fellow. After receiving his Ph.D. in Biochemistry and Molecular Biology in 1993 from Harvard University, Dr. Abel moved to the College of Physicians and Surgeons at Columbia University to do his postdoctoral work with Dr. Eric Kandel. Dr. Abel’s postdoctoral work focused on genetic approaches to study the role of protein kinase A in neuronal function. During his postdoctoral research, Dr. Abel received a fellowship from the Damon Runyon-Walter Winchell Cancer Research Fund and a young investigator award from the National Alliance for Research on Schizophrenia and Depression (NARSAD). In 1998, Dr. Abel joined the Biology Department at the University of Pennsylvania as an Assistant Professor. His lab focuses on the role of the protein kinase A signaling pathway as well as transcriptional and epigenetic regulation in memory storage, sleep/wake regulation and mouse models of psychiatric disease. As an independent investigator, Dr. Abel has received a John Merck Scholars Award and a David and Lucile Packard Fellowship in Science and Engineering. In 1999, Dr. Abel received a Young Investigator Award from the Mental Retardation and Developmental Disabilities Research Center at the Children’s Hospital of Philadelphia. In 2000, he received the Daniel X. Freedman Award from NARSAD for outstanding research by a NARSAD young investigator. Dr. Abel’s accomplishments in undergraduate teaching, research and advising were recognized in 2001 and 2005 when he was named Biological Basis of Behavior (BBB) Society Professor of the Year by the undergraduate BBB majors at Penn. In 2006, Dr. Abel was selected as the recipient of the School of Arts and Sciences Dean’s Award for Mentorship of Undergraduate Research. In 2005, Dr. Abel was elected to membership in the American College of Neuropsychopharmacology. In 2009, Dr. Abel was named the Edmund J. and Louise W. Term Professor of Biology at the University of Pennsylvania. Dr. Abel is an Associate Editor of Behavioral Neuroscience and a member of the editorial board of Hippocampus. He has been a member of the Scientific Review Council and the Board of Directors of Cure Autism Now, and served on the Scientific Advisory Committee of Autism Speaks. He has served on grant review panels for the National Science Foundation and for the National Institutes of Health (NIH), and he is currently a member of the Learning and Memory Study Section at NIH and the Scientific Advisory Board of Autism Speaks. Dr. Abel’s research has been supported by grants from the NIH, the David and Lucile Packard Foundation, Human Frontiers Science Program, the Whitehall Foundation and the John Merck Fund.
Joseph A. Beavo
University of Washington
Dr Beavo is currently a Professor of Pharmacology at the University of Washington. His interests in cyclic nucleotide phosphodiesterases started while a graduate student with Earl Sutherland and Joel Hardman at Vanderbilt University. After several years of work with Edwin Krebs on protein kinases at the University of California, Davis, he returned to studies on phosphodiesterases when he set up his own laboratory in Seattle. He has continued this interest in this area since that time.
Nicholas Brandon
Pfizer Neuroscience
Nick Brandon is currently the Head of Psychiatry Research at Pfizer. Previously he led the Schizophrenia Research group at Wyeth after starting his industry career with Merck at the Neuroscience Research Center in the UK. While at Merck Nicks work focused on identifying and validating novel targets and animal models for both schizophrenia and AD. In particular he championed efforts around glutamate based approaches for schizophrenia. He has recently spent a lot of time developing PDE inhibitor approaches for the CNS, most notably through interest in PDE10A and PDE4. In addition Nick has a keen interest in the role of risk genes and related pathways in setting up and driving disease processes and the related pathology, as exemplified through efforts around understanding the function of the risk gene Disrupted in Schizophrenia 1 (DISC1). In addition he has been very interested in the role of synapses and how they go wrong in disease and the possible approaches to rectify such deficits, as exemplified by work on estrogen. Nick was educated at Pembroke College Cambridge and did his PhD with Prof Stephen Moss at University College London on the regulation of GABAA receptors. After post-doctoral training in London he moved to Merck directly. He has published approx 50 articles.
Richard Keefe
Duke University Medical Center
Dr. Keefe is a Professor of Psychiatry & Behavioral Sciences and Psychology at Duke University Medical Center (Durham, NC). His team within Duke University is primarily devoted to understanding cognitive dysfunction in patients with schizophrenia and related disorders. It has led the development of the battery of tests for several multi-site studies of cognitive dysfunction treatment-response, including the National Institute of Mental Health (NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and the Brief Assessment of Cognition in Schizophrenia (BACS), a battery of tests that can be used in clinical trials or clinical settings to assess cognitive deficit treatment response. Dr. Keefe has been involved in several pharmacologic trials for improving cognition in schizophrenia, including a recently begun a pilot study to determine if computer-based cognitive remediation intervention is feasible and effective in a multi-site context. His group at Duke is also collaborating with the Institute of Mental Health in Singapore to complete a proof-of-concept study of the effects of pregnenolone on cognition in schizophrenia, and to investigate the cognitive and neuroanatomical factors that may predict the conversion to psychosis in young people at high risk. This project will test the hypothesis that psychosis is precipitated by impairments in memory-dependent perceptual processes.
Robin J. Kleiman
Pfizer, Inc.
Robin Kleiman received her Ph.D. in Neuroscience from the University of Virginia. Her thesis work focused on understanding mechanisms of dendritic RNA sorting and transport in cultured neurons. Her post-doctoral work at the University of California San Francisco examined receptor tyrosine kinase signal transduction, neurite outgrowth and neurotrophin-induced synaptic plasticity at the neuromuscular junction. Dr. Kleiman joined the CNS Discovery Biology group at Pfizer, Inc. in 1999. Dr. Kleiman began working with the CNS phosphodiesterase group in 2001 and has developed an interest in the role that this class of enzymes may play in Neurodegenerative and Psychiatric diseases, with a particular emphasis on the biology of PDE9 and PDE2. Her laboratory has also been involved in pathway-based identification of new drug targets including the use of imaging platforms for phenotypic screening and expression profiling for the characterization of target biology and the processes that underlie synaptic plasticity.
Jos Prickaerts
Maastricht University
Jos Prickaerts is a neurobiologist who received his PhD degree in 1998 on Memory Formation and Drugs at the Department of Psychiatry and Neuropsychology at Maastricht University. Till 2004 he worked as a post doc in multidisciplinary teams at both Maastricht University and pharmaceutical industry (e.g. Johnson and Johnson PRD, Belgium). Since 2004 he is an assistant professor working in both the Department of Psychiatry and Neuropsychology (Faculty of Health, Medicine and Life Sciences) and the Department of Neuropsychology and Psychopharmacology (Faculty of Psychology and Neurosciences) at Maastricht University. His research group focuses on signal transduction and plasticity in affective disorders and cognitive processes. In particular the role of growth factors and phosphodiesterases in this respect is being studied. Research involves working with animal models and tests in a translational context.
Lawrence P. Wennogle
Intra-Cellular Therapies, Inc.
Dr. Wennogle received his Ph.D. in Biochemistry from the University of Colorado, Boulder working under Drs. Howard Berg and Marvin Caruthers where he studied the structure of red blood cell membranes. He then completed two post-doctoral positions, one at the University of Colorado and the second at the Pasteur Institute in Paris, France, working under Jean-Pierre Changeux on the structure-function of the nicotinic acetylcholine receptor for Torpedo mamorata. For the past 29 years, Dr. Wennogle has been involved in the research and development in the pharmaceutical industry aimed at discovery of novel pharmaceutical entities for human diseases. He was a Staff Scientist and Principal Research Fellow at Ciba-Geigy and Novartis for 19 years, where he led drug discovery programs for CNS disorders, cardiovascular disease, diabetes and inflammation. Included in his experiences while at Novartis, he served on an “Expert Committee in Molecular Biology” with world-wide responsibility to evaluate new technologies. With his broad expertise in drug discovery and the biochemical basis of disease, Dr. Wennogle supervises Intra-Cellular Therapies (ITI) development of small molecule therapeutics for neurodegenerative and neuropsychiatric disorders. ITI currently has a clinical candidate for schizophrenia in phase 2 clinical trials. Dr. Wennogle is a Fellow of the New York Academy of Sciences and has co-authored over 45 scientific publications. He is a member of the New York Academy of Sciences, the American Association for the Advancement of Science, and the Society for Neurosciences. He has adjunct appointments at Columbia University in the Department of Pharmacology and at University of Medicine and Dentistry, New Jersey in the Graduate School of Biomedical Sciences. His current focus is the development of novel therapeutics for cognitive dysfunction.
Han-Ting Zhang
West Virginia University Health Sciences Center
Hanting Zhang, M.D., Ph.D., is currently an Assistant Professor of Behavioral Medicine & Psychiatry and Pharmacology at West Virginia University School of Medicine. He studies the roles of phosphodiesterases (PDEs) in intracellular signaling in the mediation of memory, depression, anxiety, and Alzheimer’s disease. He was granted NARSAD Young Investigator Awards of the US Mental Health Association in 2006 and 2008. He was the Chair of the “Phosphodiesterases in the CNS” session at the international Gordon Research Conference on PDEs (Barga, Italy) and the honored speaker at Beijing University of Chinese Medicine supported by the Ministry of Education, China, both in 2008. He has published more than 30 papers in peer-reviewed journals and 14 review articles and book chapters.
Abstracts
Cyclic Nucleotide Phosphodiesterase Regulation of Cyclic Nucleotide Function: Roles of PDE8s
Joseph A. Beavo, University of Washington
In his presentation Dr Beavo will briefly introduce the discovery and functions of cyclic nucleotide phosphodiesterases. He will then discuss some of his laboratories new data on the functional role(s) of PDE8s in brain and other organs.
PDE1 Inhibitors for Cognitive Dysfunction in Schizophrenia
Lawrence P. Wennogle, Intra-Cellular Therapies, Inc.
Hypo-function of the dopamine D1 receptor (D1R) system in the pre-frontal cortex is well established as a deficit that leads to cognitive dysfunction. This mechanism has been extensively studied in connection with schizophrenia, but is broadly implicated to other disorders of cognition. No medicines currently available address this core symptom of cognitive dysfunction. Indeed, most antipsychotic agents only worsen cognition. While direct-acting D1 dopamine receptor agonists have been developed for the treatment of cognitive dysfunction, they have not proven effective in part due to poor bioavailability. In a novel approach to enhance dopamine D1 receptor function, we have developed a series of potent and selective phosphodiesterase 1 (PDE1) inhibitors with good oral bioavailability and pharmacokinetic properties. PDE1 is enriched in the brain and highly abundant in neurons expressing dopamine D1 receptors. D1 receptors signal via stimulation of adenylate cyclase and production of cyclic-AMP. Importantly, prevention of the breakdown of cyclic-AMP by inhibition of PDE1B will result in an “on demand” potentiation of the D1R system, without perturbing dopamine receptor dynamics. PDE1 inhibitors also may enhance NMDA channel activity via modulation of a signal transduction cascade downstream of D1 receptor activation. An advanced development candidate PDE1B inhibitor has been evaluated in a number of animal models of cognition. Our development candidate is a potent (sub-nanomolar), competitive inhibitor of PDE1 with over 1000-fold selectivity for the PDE1 family over other classes of PDE enzymes. After oral administration, the agent enhances cognitive performance in rodents, as judged in the novel object recognition paradigm. It increases wakefulness, but does not disrupt pre-pulse inhibition, alter startle magnitude, influence habituation to startle response, or cause psychomotor stimulation. This candidate has no significant off-target effects, when screened against a panel of 70 unrelated receptors and enzymes. As a novel approach to treat cognitive dysfunction, this mechanism offers unique advantages over direct-acting receptor agonists. The most advanced candidate in this class is currently undergoing pre-clinical development.
PDE10A for Schizophrenia: Cell Biology to Drug Discovery
Nicholas Brandon, Pfizer Neuroscience
Phosphodiesterase 10A (PDE10A) is a dual specificity PDE, degrading both cAMP and cGMP and is remarkable for a highly enriched striatal expression pattern within so-called ‘Medium Spiny Neurons’ (MSNs). This expression pattern stimulated immediate interest in a potential role for this enzyme in treating the positive symptoms of schizophrenia. Utilizing PDE10a KO mice and an increasing repertoire of specific inhibitors it has been shown that PDE10a inhibition has a strong anti-psychotic profile in preclinical models. We will present new data showing that this mechanism also shows promising efficacy in models of cognition, and the negative symptoms of schizophrenia, two disease domains that are underserved by current treatments. To this end we will present data with the compounds MP-10, which has entered clinical development, papaverine and a novel compound known as WEB-3. Specifically these compounds show an ability to increase sociality in BALB/cJ mice in the Social Approach/Social Avoidance assay, reverse the effects of chronic MK-1801 treatment in a forced swim test, enhance social odor recognition in mice, and improve novel object recognition in rats. We will also present data confirming their anti-psychotic profile and exploring the neurochemical correlates of these effects. In addition we have been very interested in understanding the cellular effects of these compounds in the brain. In particular we have seen that they regulate the phosphorylation status of a panel of glutamate receptor subunits in the striatum. Strikingly PDE10A inhibition increased the phosphorylation of the AMPAR GluR1 subunit at residue serine 845 at the cell surface. In addition we have investigated the cell biology of this enzyme and will show that phosphorylation and palmitoylation of PDE10A are critical to determine the subcellular localization of the enzyme. The relationship of small molecule inhibition to such dynamic processes will be discussed. Together, our results will suggest that PDE10A inhibitors show broad spectrum efficacy in pre-clinical models and will provide insight into mechanisms of action of these compounds.
Comparison of PDE9 and PDE10 Inhibitors in Preclinical Schizophrenia Models
Robin J. Kleiman, Pfizer, Inc.
Regulation of central cGMP signaling cascades via inhibition of PDE9 or PDE10 have both been proposed as therapeutic approaches to treatment of various symptom domains associated with schizophrenia. This talk will compare and contrast the preclinical profile of PDE9 and PDE10 inhibitors in models of psychosis, cognition and will highlight alternative changes in gene expression profiles induced by selective inhibitors of PDE9 and PDE10 following chronic treatment.
Overview of Cognition in Schizophrenia
Richard Keefe, Duke University Medical Center
Neurocognition is severely impaired in patients with schizophrenia independent of phase of illness. While these impairments may appear prior to the onset of psychosis, their severity in chronic schizophrenia patients is about 1.5 to 2.0 standard deviations below the healthy population. Neurocognitive impairment is a central clinical feature of schizophrenia, as it is strongly associated with functional outcomes. Antipsychotic medications have minimal impact on cognition, and no drug has yet been approved for cognitive enhancement purposes for schizophrenia. NIMH established the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative to stimulate the development of drugs to treat cognitive deficits in schizophrenia. As part of this initiative, the MATRICS Consensus Cognitive Battery (MCCB) was developed for assessing cognitive change in clinical treatment studies. However, to meet the need for more precise assessment instruments for measuring changes in specific cognitive functions in treatment studies, cognitive neuroscience methods with known linkages to specific brain systems, and to some extent their biochemistry, provide a logical alternative assessment strategy for identifying specific cognitive impairments to be targeted in schizophrenia treatment trials. FDA representatives have made clear their intention to require that a new drug for cognitive enhancement in schizophrenia demonstrate not only a cognitive benefit, but a clinically meaningful improvement in functional capacity as a co-primary measure in such treatment studies.
PDE Inhibitors and Cognitive Function: What We can Learn about Mechanisms Involved
Jos Prickaerts, Maastricht University
Phosphodiesterase (PDE) inhibitors have been identified as possible cognition enhancers about a decade ago. Rodent studies with different timing of treatment with specific PDE inhibitors indicated that distinct underlying signaling pathways for early and late consolidation processes exist corresponding to specific time-windows for memory consolidation. There is evidence that the underlying mechanisms of PDE inhibition on the observed behavioral effects are independent of possible cerebrovascular effects. Recently, the effects of specific PDE inhibitors are explored on other cognitive domains including acquisition processes/short-term memory and information processing. Studies on the effects of specific PDE inhibitors on information processing by using a sensory gating paradigm are in progress. Within the context as described above, the latest results of specific inhibitors of PDE2, PDE5, PDE9 and PDE10 on cognitive function will be presented and discussed.
cAMP Signaling in Mouse Models of Psychiatric Disorders
Ted Abel, University of Pennsylvania
Recently, a polymorphism that increases mRNA levels of the G-protein subunit Galphas was genetically linked to schizophrenia. Here I will discuss our findings that regulated overexpression of Galphas mRNA in forebrain neurons of mice is sufficient to cause a number of schizophrenia-related phenotypes, as measured in adult mice, including sensorimotor gating deficits (prepulse inhibition of acoustic startle, PPI) that are reversed by haloperidol or the phosphodiesterase inhibitor rolipram, psychomotor agitation (hyperlocomotion), hippocampus-dependent learning and memory retrieval impairments (hidden water maze, contextual fear conditioning), and enlarged ventricles. Interestingly, overexpression of Galphas during development plays a significant role in some (PPI, spatial learning and memory and neuroanatomical deficits) but not all of these adulthood phenotypes. Pharmacological and biochemical studies suggest the Galphas-induced behavioral deficits correlate with compensatory decreases in hippocampal and cortical cyclic AMP (cAMP) levels. I will also discuss our recent findings of the role of cAMP signaling in the cognitive deficits that occur following sleep deprivation.
PDE4 Isoenzymes in Memory
Han-Ting Zhang, West Virginia University Health Sciences Center
Phosphodiseterase-4 (PDE4) has been implicated in the mediation of memory, however, it is not known which of the four PDE4 subtypes (PDE4A, B, C, and D) is (are) involved primarily because of the lack of highly selective inhibitors of individual PDE4 subtypes. Using mice deficient in a specific PDE4 subtype, we demonstrated that PDE4D is the major subtype responsible for memory. Further studies using RNA interference (RNAi) revealed that PDE4D4 and PDE4D5 are important splice variants in mediating memory in normal and amyloid 1-42-treated animals. Therefore, targeting PDE4D, particularly its PDE4D4/5 variants, may be a novel approach to the treatment of disorders affecting cognition such as Alzheimer’s disease.
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