WO2012106404A2 - Diagnostic et traitement de troubles neurologiques par vipr2 et vpac2r - Google Patents

Diagnostic et traitement de troubles neurologiques par vipr2 et vpac2r Download PDF

Info

Publication number
WO2012106404A2
WO2012106404A2 PCT/US2012/023445 US2012023445W WO2012106404A2 WO 2012106404 A2 WO2012106404 A2 WO 2012106404A2 US 2012023445 W US2012023445 W US 2012023445W WO 2012106404 A2 WO2012106404 A2 WO 2012106404A2
Authority
WO
WIPO (PCT)
Prior art keywords
vpac2r
vipr2
gene
patient
receptor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2012/023445
Other languages
English (en)
Other versions
WO2012106404A3 (fr
Inventor
Janathan SEBAT
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California Berkeley
University of California San Diego UCSD
Original Assignee
University of California Berkeley
University of California San Diego UCSD
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of California Berkeley, University of California San Diego UCSD filed Critical University of California Berkeley
Publication of WO2012106404A2 publication Critical patent/WO2012106404A2/fr
Publication of WO2012106404A3 publication Critical patent/WO2012106404A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • This invention provides diagnostic and therapeutic methods to detect and treat neurological disorders, such as schizophrenia, autism, and other related disorders.
  • CNVs Rare copy number variants
  • Substantial risk for schizophrenia is conferred by large (>500 kb) CNVs at several loci, including microdeletions at lq21.1 z , 3q29 15q I3.3 2 and 22q l 1.2 - and microduplication at 16pl 1.2
  • these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood.
  • a majority of the rare CNVs that have been implicated in schizophrenia involve large (> 500 Kb) genomic regions where local segmental duplication architecture promotes frequent and nearly identical rearrangements by non-allelic homologous recombination (NAHR). Because of the high structural mutation rates at these loci, the strong phenotypic effects of the causal variants, and the excellent power of most array platforms to detect such large CNVs, these genomic hotspots were the first to be detected in studies of CNVs in schizophrenia.
  • NAHR non-allelic homologous recombination
  • NRXN1 Neurexin-1
  • NRXN 1 deletions are not flanked by segmental duplications, and may occur by different mutational mechanisms such as non-homologous end joining (NHEJ) or DNA replication-mediated rearrangement.
  • VIPR2 encodes the vasoactive intestinal peptide (VIP) receptor VPAC2, a
  • VPAC2 binds VIP u , activates cyclic-AMP signaling and PKA, regulates synaptic transmission in the hippocampus i & and promotes the proliferation of neural progenitor cells in the dentate gyrus ' ⁇ . Genetic studies in mouse have established that VIP signaling plays a role in learning and memory— . VPAC2 also plays a role in sustaining normal circadian oscillations in the SCN ⁇ ⁇ , and VIPR2-null " ⁇ and VlPR2-overexpression ⁇ mice exhibit abnormal rhythms of rest and activity.
  • VIPR2 is known to play a role in the cardiovascular and gastrointestinal system, and it is this application that has driven early efforts to develop selective agonists , and antagonists of VPAC2R.
  • Peptide derivatives 26 and small molecules— have been identified that are selective VPAC2 agonists or antagonists
  • This invention provides diagnostic and therapeutic methods and compositions to detect and treat neurological disorders, such as schizophrenia, autism, and other related disorders through modulating vasointestinal peptide receptor 2 gene (VIPR2) expression or correcting pathogenic mutations of the VIPR2 gene, and/or through modulating the VIPR2 encoding vasointestinal peptide 2 receptor (VPAC2R) activity in the cyclic-AMP signaling with selective VPAC2R agonists, VPAC2R antagonists, and/or VIP or peptide derivatives thereof.
  • VIP2R vasointestinal peptide receptor 2 gene
  • the present invention provides novel generic r_ methods for the; identification of patients that carry mutations in VIPR2, and further detection of mutations in DNA that impact the function of VIPR2. These methods include, but are not limited to, microarray, PCR and mass spectrometry based methods.
  • the present invention further provides that the patients carrying the mutations in VIPR2 can benefit from treatment with selective agonists or antagonists of VPAC2R, and/or VIP or peptide derivatives.
  • the present invention further provides diat mutations in DNA that modify the expression of the V1PR2 gene are pathogenic.
  • the pathogenic mutations include, but arc not limited to, copy number variants (CNVs), which can be detected using multiple methods that have been developed. These methods include, but are not limited to, ,. microarray analysis and computational methods for analysis of microarray data, PCR and Mass Spectrometry based detection.
  • CNVs copy number variants
  • the present invention further provides that other mutations of the VIPR2 genomic region, including CNVs, indels and single nucleotide variants can be detected by DNA sequencing.
  • the present invention also provides that ovcrcxpression of the
  • Vasointestinal Peptide Receptor 2 (V1PR2) gene confers a high risk of a neurological : disorder, such as schizophrenia and autism.
  • V1PR2 Vasointestinal Peptide Receptor 2
  • specific compounds that selectively modulate the activity of the VPAC2R receptor that is encoded by VIPR2, including selective agonists, antagonists, VIP, and/or VIP peptide derivatives, are provided as treatments for these and related disorders.
  • the present invention provides the first conclusive genetic link between VIPR2 and disorders of the brain, and for the first time the pathogenic mechanism of V1PR2 including alterations in the c expression of the VIPR2 gene and alterations in cyclic-AMP signaling by the VPAC2 receptor.
  • the present invention provides the application of selective antagonists and agonists in the treatment of neurological disorders, including, but not limited to schizophrenia, autism, and related disorders.
  • the present invention provides that treatment effective amounts of antagonists of VPAC2R, .:; such as compounds I and 2 published by Chu et al. peptide derivatives of VIP published by Moreno et al.— , such as selective antagonists PG-96-238 and PG-99-465, and partial agonist PG-97-277 and PG-97-278, modulate the activity of VIPR2, consequently modulate the disease process.
  • the present invention provides that a synthetic peptide and a selective agonist, BAY-55-9837, modulates the pathogenic activity of VIPR2 in human cells.
  • the present invention demonstrates that VIP and BAY 55-9837, a peptide derivative of VIP that selectively binds to VPAC2, elicit a high level of cyclic-AMP accumulation in lymophoblastoid cell lines of patients with pathogenic mutations of V1PR2.
  • the cAMP accumulation observed in patients is significantly higher than in controls, indicating that the pathogenic mechanism of VIPR2 mutations is modulated by compounds active against the VPAC2 receptor. Therefore, the present invention provides that the pathogenic action of VIPR2 can be corrected by treatment with these and related compounds or peptides.
  • a patient, in which human cells are overexpressing VIPR2 can be treated with a selective antagonist of VPAC2.
  • a patient in which human cells are underexpressing VIPR2 can be treated with VIP or another selective agonist of , ⁇ VPAC2, such as «AY 55-9837.
  • the present invention further provides a novel approach to using genetic testing to guide the selection of appropriate drugs for modulation of VPAC2R activity and consequently to treat neurological disorders, such as schizophrenia and autism.
  • the present invention provides that copy number of the V1PR2 is directly correlated with VPAC2R activity, and thus a genetic test can be used for gene copy number to infer the ⁇ ' effect of mutations on gene function.
  • a therapeutic strategy is provided whereby molecular testing of human cells can be effectively used to guide the selection of appropriate drugs for individual patients.
  • overexpression or underexpression of VIPR2 is detected through genetic analysis of DNA and RNA from human cells. Changes in VPAC2 activity are detected through analysis of cyclic-AMP accumulation in human cells. The efficacy of drug candidates is evaluated by monitoring DNA and RNA while treatment of human cells with drug candidates in culture.
  • Human cells include, but are not limited to, blood, lymphoblastoid cell lines, fibroblasts, induced pluripotent stem cells (iPSCs) or cell types derived from iPSCs.
  • the novel approach to personalized treatment of schizophrenia and/or autism consists of applying the diagnostic and therapeutic inventions described above to the analysis of DNA and human cells from patients. Genetic analysis of DNA, biochemical analysis of V1PR2 expression, biochemical analysis of VPAC2 activity in human cells are used to infer the pathogenic mechanism (underexpression or overpression of VIPR2). Having determined the pathogenic mechanism, appropriate drugs are selected based on their ability to rescue VPAC2 activity in human cells from the patient. Appropriate drugs are selected based on their ability to rescue animal behavior in VIPR2 genetic mouse models, including a VIPR2 knockout and a VIPR2 expression mouse.
  • the present invention therefore provides that treatment of patients with compounds or peptides active against VPAC2 can be significantly improved using the diagnostic and personalized medicine of the present inventions provided herein.
  • Selective antagonists or agonists of VPAC2 that are known to or later discovered to modulate the disease process appropriately in the in vitro and in vivo systems constitute new antipsychotic drugs for the treatment of schizophrenia, autism and related disorders.
  • A. research tool model for identifying a therapeutic candidate and/or drug leads for treatment, diagnosis, prognosis or prevention of schizophrenia or autism in a mammal is also provided by the present invention.
  • the present invention provides molecular assays of human cells for testing the efficacy of drug leads or candidates in vitro, in certain embodiments, the present invention provides appropriate genetic mouse models of VIPR2 for testing the efficacy of drug leads in vivo.
  • FIG. 1 Duplications and triplications of 7q36.3 result in increased VIPR2 transcription and cyclic-AMP signaling,
  • FIG. 3 Structure of VPAC2 antagonist hits compounds 1 and 2.
  • the full name of compound 1 is (2R,4S)-2-benzyl-4-hydroxy-N-((ls,2R)-2-hydroxy-2,3-dihydro- lH-inden-l-yl)5-(4-nitrophenylsulfonamido)pcntanamide.
  • the full name of compound 2 - is (2R,4S)-2-benzyl-5-(4 ⁇ ert-but>dphenylsulfonainido)-4-hydro-N-((lS J 2R)-2-hydroxy- 2,3-dihydro-lH-inden-I -yl)pentan amide.
  • the present invention provides a novel approach for diagnosis and personalized treatment of neurological disorders, such as schizophrenia, autism, or other related neurological disorders by detecting one or more pathogenic mutations or an abnormal gene expression level of VIPR2 in the patient, then treating the patient with an effective amount of a modulator that is able to correct the pathogenic effect of the mutations, modulating the VIPR2 gene expression, resulting in modulating the activity of VPAC2R in the cyclic AMP signaling functions.
  • the present invention also provides a novel approach for diagnosis and personalized treatment of neurological disorders, such as schizophrenia, autism, or other related neurological disorders by modulating VPAC2R activity directly with an effective amount of selective VPAC2R agonists, VPAC2R antagonists, and/or VIP or peptide derivatives or analogs thereof.
  • the present invention provides a method and composition for treatment of a neurological disorder comprising administering to a patient in need a treatment effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically active agent selected from the group consisting of a selective antagonist and or agonist of vasoactive intestinal peptide 2 ,. receptor (VPAQ2R), a modulator of VPAC2R or VPAC2R gene (aka VIPR2), and a vasoactive intestinal peptide (VIP) derivative or analog.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically active agent selected from the group consisting of a selective antagonist and or agonist of vasoactive intestinal peptide 2 ,. receptor (VPAQ2R), a modulator of VPAC2R or VPAC2R gene (aka VIPR2), and a vasoactive intestinal peptide (VIP) derivative or analog.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically active agent selected from the group consisting of a selective antagonist
  • VPAC2R vasoactive intestinal peptide
  • PACAP putuitary adenylate cyclase-activating peptide
  • VPAC2R vasoactive intestinal peptide 2 receptor
  • the degree of selectivity is determined by a ratio of VPAC2 receptor binding affinity to VPAC I receptor binding affinity and by a ratio of VPAC2 receptor binding affinity to PAC 1 receptor binding affinity.
  • the agonists of the present invention have a selectivity ratio where the affinity for the VPAC2 receptor is at least 50 times greater than for the VPACl and/or for PACl receptors. More preferably, the affinity is at least 100 times greater for VPAC2 than for VPACl and/or for PACl . Even more preferably, the affinity is at least 200 times greater for VPAC2 than for VPACl and/or for PACl . Still more preferably, the affinity is at least 500 times greater for VPAC2 than for VPACl and/or for PACl. Yet more preferably, the affinity is at least 1000 times greater for VPAC2 than for VPAC 1 and or for PAC 1.
  • VPAC2 receptor vasoactive intestinal peptide
  • PACAP vasoactive intestinal peptide
  • the selective antagonist or agonist of VPAC2 receptor includes, but is not limited to, now known or later developed peptide and/or chemical compounds that show selectively high binding affinity to the VPAC2 as compared to the binding affinity to the other known receptors, such as VPACl and PAC l.
  • Exemplary selective VPAC2 receptor antagonists and agonists are disclosed in literature, such as Chu et al.
  • VPAC2 receptor antagonists are compound 1 and compound 2 with the chemical structures shown in Figure 3, and ,. derivatives and analogs thereof.
  • VIP refers to naturally occurred vasoactive intestinal peptide (VIP) having a single amino acid sequence containing 28 naturally occurred amino acids.
  • naturally occurring amino acid as used herein means the twenty amino acids coded for by the human genetic code (i.e. the twenty standard amino acids). These twenty amino acids are: Alanine, Arginine, Asparagine, Aspartic : ⁇ Acid, Cysteine, s Glutamine, Glutamic Acid, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine and, Valine.
  • VIP derivative or analog refers to peptides or compounds that differ from naturally occurred VIP amino acid sequence by substitution, addition or removal of one or more amino acid.
  • the amino acid used for substitution or addition can be either naturally occurring amino acids as defined above, or non-naturally occurring amino acids, which include both synthetic amino acids and those modified by the body. These include D-amino acids, arginine-like amino acids (e.g., homoarginine), and other amino acids having an extra methylene in the side chain (“homo" amino acids), and modified amino acids (e g norlcucine, lysine (isopropyl)-- wherein the side chain amine of lysine is modified by an isopropyl group). Also included are amino acids such as ornithine and amino isobutyric acid.
  • the VIP derivatives and/or analogs include, but are not limited to, those that are widely known in the art or later developed.
  • Exemplar)' known VIP derivatives and/or analogs are natural VIP related peptides, such as hclodermin and helospectin which are isolated from the salivary excretions of the Gila Monster - (Heloderma Suspectum); the VIP peptide analogs disclosed in W091/06565 comprising a combination of the amino acid sequence of VIP with a part of the amino acid sequence of helodermin; and linear or cyclic VIP analogies (see e.g., US Patent No. 5,677,419; EP 0536,741 ; US Patent Nos.
  • the VIP derivatives or ' analogues are selective VPAC2 receptor peptide antagonist or partial agonist developed from the cyclic VIP analogues as starting point, such selective VPAC2 receptor peptide antagonists or partial agonists include, but arc not limited to, PG 96-238, PG 99-465, PG 97-277, and PG 97-278 (see e.g., Moreno et al., 2000, Peptides, 21 : 1543-49).
  • the amino acid sequences of these selective VPAC2 receptor peptide antagonist or partial agonist are shown in Figure 4.
  • the term “modulator” refers to any compounds and/or peptides, naturally occurring or synthetically synthesized, that provide any effect on the VPAC2 protein expression or the activity of the VPAC2 receptor or the expression or the activity of at least one protein involved in VPAC2 receptor induced c-AMP signaling pathway.
  • modulator also refers to any compounds and/or peptides, naturally occurring or synthetically synthesized, that provide any effect on the expression, the activity, and/or correction of pathogenic mutations of the VIPR2 gene encoding the VPAC2 receptor protein.
  • the "effect” as used herein refers to optionally a partial or complete stimulation, but preferably a partial or complete inhibition.
  • the modulator as used herein preferably inhibits the expression or the activity of VPAC2 receptor and/or at least one proteins involved in the VPAC2 receptor induced c-AMP signaling pathway, or inhibits die VIPR2 gene expression or corrects one or more pathogenic mutations, "including but not limited to, copy number variants (CNVs), duplications, indels, or single nucleotide variants of V1PR2 gene.
  • VIP2 gene expression is intended to mean the amount of mRNA of VIPR2 expressed
  • VPAC2 protein expression is intended to mean the amount of VPAC2 protein expressed.
  • the modulator is a VPAC2R or VPAC2 signaling pathway inhibitor.
  • inhibitor refers to a chemical compound or substance which eliminates or substantially reduces the biological activity of the VPAC2R or VPAC2 signaling pathway proteins.
  • substantially signifies a reduction of at least 25%, preferably of at least 35%,' even more preferably of at least 50%, and more preferably at least 70% or 90%.
  • the modulator as used herein may be of any type. They may be of natural origin or may have been produced by chemical synthesis.
  • the modulator may be an inhibitory anti-VPAC2R or anti-VPAC2R-signalling pathway antibody, including a monoclonal antibody.
  • the modulator may also be a polypeptide, an antisense D A or RNA polynucleotide, an si- RNA, or a PNA (Peptide nucleic acid, polypeptide chain substituted with purine and pyrimidine bases, the spatial structure of which mimics that of the DNA and allows hybridization thereto).
  • the modulator may also be an aptamer.
  • the aptamer is a class of molecules representing, in terms of molecular recognition, an alternative to antibodies.
  • ligands are oligonucleotide sequences having the ability to recognize virtually all classes of target molecules with high affinity and specificity.
  • ligands can be isolated by systematic evolution of ligands by exponential enrichment (SELEX) of a random sequence library as described by Tuerk and Gold (1990, Science 249: 505-510).
  • the random sequence library can be obtained by combinatorial chemical DNA synthesis.
  • each member is an optionally chemically modified linear oligomer of a single sequence. Possible modifications, uses and advantages of this class of molecules have been reviewed in Jayasena (1999, Clinical Chemistry 45(9): 1628-1650).
  • the term "pharmacologically active agent,” “therapeutic agent,” “active agent,” or “drug” is used interchangeably to refer to a chemical material or compound that induces a desired pharmacological, physiological effect, and include agents that are therapeutically or prophylactically effective.
  • the terms also encompass pharmaceutically acceptable, pharmacologically active derivatives and analogs of those active agents specifically mentioned herein, including but are not limited to, salts, esters, amides, prodrugs, active metabolites, inclusion complexes, analogs, and the like.
  • pharmaceutically active agent “active agent,” and “drug” are used, it is to be understood that applicants intend to include the active agent per sc as well as pharmaceutically. acceptable, pharmacological ly active salts, esters, amides, prodrugs, active metabolites, inclusion complexes, analogs, etc., which are collectively referred to herein as "pharmaceutically acceptable derivatives”.
  • the pharmaceutically active agents as used herein may also refer to any oligonucleotides (antisensc oligonucleotide agents), polynucleotides (e.g. therapeutic DNA), ribozymes, dsRNAs, siRNA, RNAi, gene therapy vectors, and/or vaccines for :; therapeutic use.
  • antisensc oligonucleotide agents refers to short synthetic segments of DNA or RNA, usually referred to as oligonucleotides, which are designed to be complementary to a sequence of a specific mRNA to inhibit the translation of the targeted mRNA by binding to a unique sequence segment on the mRNA.
  • Antisense oligonucleotides are often developed and used in the antisense technology.
  • the term "antisense technology” refers to a drug-discovery and development technique that involves design and use of synthetic oligonucleotides complementary to a target mRNA to inhibit production of specific disease-causing proteins. Virtually all diseases are associated with inadequate or over-production of proteins. Traditional small molecule drugs are designed to interact with disease-causing proteins and inhibit their function. ⁇ contrast, antisense technology permits design of drugs, called antisense oligonucleotides, which intervene at the genetic level and inhibit the production of disease-associated proteins. Antisense oligonucleotide agents are developed based on genetic information.
  • ribozymes or double stranded RNA can also be used herewith as pharmaceutically active agents.
  • dsRNA double stranded RNA
  • RNAi RNA interference
  • siRNA small interfering RNA
  • ribozyme refers to a catalytic RNA-based enzyme with ribonuclease activity that is capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which it has a complementary region. Ribozymes can be used to catal tically cleave target mRNA transcripts to thereby inhibit translation of target mRNA.
  • RNA refers to RNA hybrids comprising two strands of RNA.
  • the dsRNAs can be linear or circular in structure.
  • the dsRNA may comprise ribonucleotides, ribonucleotide analogs, such as 2'-0-methyl ribosyl residues, or combinations thereof.
  • RNAi refers to RNA interfernce or post-transcriptional gene silencing (PTGS).
  • siRNA refers to small dsRNA molecules (e.g., 21-23 nucleotides) that arc the mediators ⁇ ;: of the RNAi effects.
  • RNAi is induced by the introduction of long dsRNA (up to 1 -2 kb) produced by in vitro transcription, and has been successfully used to reduce gene expression in variety of organisms.
  • RNAi uses siRNA (e.g. 22 nucleotides long) to bind to the RNA-induced silencing complex (RISC), which then binds to any matching mRNA sequence to degrade target mRNA, thus, silences the gene.
  • siRNA e.g. 22 nucleotides long
  • RISC RNA-induced silencing complex
  • the pharmaceutically active agents also include any vectors/virus useti for gene therapy.
  • gene therapy refers to a technique for correcting defective genes responsible for disease development. Such techniques may include inserting a normal gene into a nonspecific location within the genome to replace a nonfunctional gene; swapping an abnormal gene for a normal gene through homologous recombinations, reparing an abnormal gene to resume its normal function through selective reverse mutation; and altering or regulating gene expression and/or functions of a particular gene.
  • a normal gene is inserted into the genome to replace an abnormal or disease-causing gene.
  • a term "vector/virus” refers to a carrier molecule that carries and delivers the "normal" therapeutic gene to the patient's target cells. Because viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner, mostcommon vectors for gene therapy are viruses that have been genetically altered to carry the normal human DNA. As used herein, the viruses/vectors for gene therapy include retroviruses, adenoviruses, adeno- associated viruses, and herpes simplex viruses.
  • retrovirus refers to a class of viruses that can create double-stranded DNA copies of their RNA genomes, which can be further integrated into the chromosomes of host cells, for example, Human immunodeficiency virus (HIV) is a retrovirus.
  • HIV Human immunodeficiency virus
  • adenovirus refers to a class of viruses with double-stranded DNA genomes that cause respiratory, intestinal, and eye infections in human, for instance, the virus that cause the common cold is an adenovirus.
  • adenci-associated vims refers to a class of small, single-strandcd DNA viruses that can insert their genetic material at a specific site on chromosome 19.
  • Herpes simplex viruses refers to a class of double-stranded DNA viruses that infect a particular cell type, neurons. Herpes simplex virus type I is a common human pathogen that causes cold sores.
  • a term “treatment effective amount” refers to the quantity that results in a desired therapeutic and/or prophylactic effect without causing unacceptable side effects when administered to a patient in need of the invention ⁇ : pharmaceutical composition.
  • a “desired therapeutic effect” includes one or more of the following: 1 ) an amelioration of the symptom(s) associated with the disease or condition; 2) a delay in the onset of symptoms associated with the disease or condition; 3) increased longevity compared with the absence of the treatment; and 4) greater quality of life compared with the absence of the treatment.
  • an "treatment effective amount" of a VPAC2 receptor antagonist for the treatment of schizophrenia is the quantity criz that would result, in greater control of symptoms associated with schizophrenia dian in the absence of treatment.
  • a "treatment effective amount” as used herein will also depend on the type and severity of the disease and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs.
  • the dose of the invention composition administering to a patient in need will depend on a number of factors, among which are included, without limitation, the patient's sex. weight and age, the type and or severity of the disease, die route of administration and bioavailability, the pharmacokinetic profile of the agent, the potency, the formulation, and other factors within the particular knowledge of the patient and physician. Thus, it is not necessary to specify' an exact effective amount herein. However, an appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • an effective amount of an active agent incorporated into a composition or dosage form of the present invention is not critical, so long as the concentration is within a range sufficient to permit ready application of the solution or formulation so as to deliver an amount of the active agent that is within a therapeutically effective range.
  • solutions are homogeneous mixtures prepared by dissolving one or more chemical substances (solute) in another liquid such that the molecules of the dissolved substance are dispersed among those of the solvent.
  • the solution may contain other pharmaceutically acceptable chemicals to buffer, stabilize or preserve the solute.
  • solvents used in preparing solutions are saline, water, ethanol, propylene glycol or any other pharmaceutically acceptable vehicle.
  • a typical dose range for the therapeutic composition of the present invention will range from about ⁇ g per day to about 5000 ⁇ per day.
  • the dose ranges from about 1 per day to about 2500 ⁇ g per day, more preferably from about 1 g per day to about 1000 ug per day.
  • the dose ranges from about 5 ug per day to about 100
  • a person skilled in the art will take care of select the suitable amount of the invention composition, such that a desired therapeutic and/or prophylactic effect is obtained without causing unacceptable side effects when administered to a patient in need of the invention pharmaceutical composition.
  • the term "pharmaceutically acceptable carrier” refers to carrier materials suitable for administration of a pharmaceutically active agent. Carriers useful herein include any such materials known in the art, which are nontoxic and do not interact with other components of the composition in a deleterious manner. Various additives, known to those skilled in the art, may be included in the composition of the present invention.
  • solvents including relatively small amounts of alcohol, may be used t3 ⁇ 4 solubilize certain drug substances.
  • Other optional additives include opacifiers, antioxidants, fragrance, colorant, gelling agents, thickening agents, stabilizers, surfactants and the like.
  • Other agents may also be added, such as antimicrobial agents, to prevent spoilage upon storage, i.e., to inhibit growth of microbes such as yeasts and molds.
  • Suitable antimicrobial agents are typically selected from the group consisting of the methyl and propyl esters of p-hydroxybenzoic acid (i.e., methyl and propyl paraben), sodium benzoate, sorbic acid, imidurea, and combinations thereof.
  • the pharmaceutically active agent may be administered through any desirable route, such as oral and/or any parental administration, if desired, in the form of a salt, ester, amide, prodrug, derivative, or the like, provided the salt, ester, amide, prodrug or derivative is suitable pharmacologically.
  • Salts, esters, amides, prodrugs and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the ar ⁇ of synthetic organic chemistry and described, for example, by March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th Ed. (Wiley- Interscience, 2001). Preparation of salts, ester, amides, prodrug, etc. is known to those skilled in the art or described in the pertinent literature. [0042)
  • the invention composition is preferably administered to a human.
  • the invention composition can also be administered to any mammals including animal, e.g., companion animals (e.g.. dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • animal e.g., companion animals (e.g. dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • a subject of the invention relates to an in vitro method for diagnosing, determining an individual's susceptibility to developing, or monitoring the progression of a neurological disorder, such as schizophrenia or autism, in a patient, which comprises the steps of a) obtaining a biological sample from said patient; b) detecting one or more pathogenic mutation, such as copy number variants (CNVs), duplications, indels, or single nucleotide variants, or an expression level of V1PR2 gene in said biological sample; and c) diagnosing said patient being at risk for said neurological disorder wherein one or more pathogenic mutation or overexpressed level of VIPR2 gene is detected in said biological sample of said patient.
  • CNVs copy number variants
  • the present invention also contemplates an in vitro method for diagnosing or monitoring the progression of a neurological disorder in a patient comprising comparing the expression or activity of VPAC2R and/or at least one of the VPAC2R signaling pathway proteins in a biological sample from a patient, relative to a biological sample from a control individual.
  • VPAC2R signaling pathway proteins according to one of the methods such as Western blotting, immunohistochemistry, analysis by mass spectrometry (Maldi-TOF and LC/MS analysis), radioimmunoassay (RIA) and ELISA or any other method known to those skilled in the art.
  • Another method, in particular for measuring the expression of VIPR2 or VPAC2R signaling pathway gene is to measure the amount of the corresponding mRNA by any method such as RT-PCR, ribonuclease protection assay, ⁇ : northern blotting; hybridisation-based microarray technologies or any other method known to those skilled in the art.
  • control individual is a "healthy” individual.
  • control individual refers to the same individual at a different time, which preferably corresponds to the beginning of the treatment (TO).
  • This ' ⁇ ⁇ " measurement of the difference in expression or in activity of VPAC2R or at least one of the VPAC2R signaling pathway proteins, or in expression or mutation(s) of die VIPR2 gene or in activity of VIPR2 or at least one of VPAC2R signaling pathway genes makes it possible in particular to monitor the efficacy of a treatment, in particular a treatment with a pharmaceutically active agent, as envisaged above, or another treatment against the neurological disorder. Such monitoring can reassure the patient as to the well-founded _ grounds or the need for continuing this treatment.
  • the biological sample tested may be any sample of biological fluid or a tissue sample obtained by invasive or non-invasive methods.
  • the biological sample is a brain tissue or cell obtained from a patient in need.
  • the present invention also provides an in vitro or in vivo method or a research tool model for identifying compounds which arc therapeutic candidates for treatment, diagnosis, prognosis or prevention of a neurological disorder, such as schizophrenia or autism, in a patient, comprising comprises combining the therapeutic candidate with a VIPR2 gene or other genes encoding at least one of the VPAC2R signaling pathway proteins, and observing or determining modulation of VIPR2 gene expression or correction of pathogenic mutations, such as copy number variants (CNVs), duplications, indels, or single nucleotide variants of the VIPR2 gene, said modulation indicating the usefulness of the therapeutic candidate for treatment, diagnosis, prognosis or prevention of a neurological disorder, such as schizophrenia or autism.
  • CNVs copy number variants
  • indels or single nucleotide variants of the VIPR2 gene
  • the present invention also provides an in vitro or in vivo method or a research tool model for identifying compounds which are therapeutic candidates for treatment, diagnosis, prognosis or prevention of a neurological disorder, such as : schizophrenia or autism, in a patient, comprising comprises combining the therapeutic candidate with VPAC2R or at least one of VPAC2R signaling pathway proteins, and observing or determining modulation of VPAC2R expression and/or activity in cyclic- AMP signaling, said modulation indicating the usefulness of the therapeutic candidate for treatment, diagnosis, prognosis or prevention of a neurological disorder, such as schizophrenia or autism.
  • a neurological disorder such as : schizophrenia or autism
  • the therapeutic candidates are compounds of any type. They may be of natural origin or may have been produced by chemical synthesis. They may be a library of structurally defined chemical compounds, of non-characterized compounds or substances, or a mixture of compounds. Various techniques can be used to test these compounds and .. to identify the compounds of therapeutic interest which are antagonist or agonist of VPAC2R, modulators of VPAC2R or VIPR2, or VIP derivatives or analogs thereof. [0049] An in vivo screening method can be carried out in any laboratory animal, for example a rodent.
  • the screening method comprises administering the test compound to the animal, then optionally sacrificing the animal by euthanasia and taking a suitable biological sample before evaluating the expression and/or mutations of the 'VIPR2 gene, or expression or activity of its encoding V AC2R or at least one of the VPAC2R signaling pathway proteins, by any method described herein.
  • the initial discovery data set was composed of 1,761 unrelated subjects analyzed on the NimbleGcn HD2 Array-CGH platform.
  • the unfiltcred sample consisted of 913 patients and 848 controls ascertained at ten sites. Ascertainment of these samples for family-based studies is described in previous publications 24: i .
  • Microarray - hybridizations using the NimbleGen HD2 platform were performed at the service laboratory of Roche NimbleGen according to the manufacturer's specifications. Samples were filtered from the dataset based on data quality measures described below. Five duplicate samples from Trinity College Dublin also present in the ISC dataset were removed from the primary dataset.
  • the final discovery data set consisted of 906 unrelated patients and 742 controls.
  • NimbleGen HD2 With the exception of data collected by ISC, all processing of microarray data was performed at Cold Spring Harbor Laboratory. Different methods were used for dual color intensity data from NimbleGen HD2 and single color intensity data from the Affymetrix Genome-Wide Human SNP 6.0 genotyping array. a) NimbleGen HD2
  • NimbleGen HD2 dual color intensity data were normalized in a two step process: (1) a spatial normalization of probes was performed to adjust for regional differences in intensities across the surface of the array, and (2) the Cy5 and Cy3 intensities were adjusted to a fitting curve by invariant set normalization.
  • Invariant set normalization of intensity data involves selection of a probe set with minimal variability between the ranked test and reference autosomal probe intensities as described in Li et al The test intensities of this invariant autosomal probe set are then adjusted to the reference distribution. Based on these adjustments, a fitting curve is established to which all other intensities are shifted, preserving the variability in the data. The intensities of X and Y chromosomes were then extrapolated to the fitting curve. The process is repeated while exchanging the test and
  • SNP Array single color intensity data (Affymetrix 500K, Affymetrix 5.0 & Affymetrix 6.0).
  • All arrays were normalized by invariant set normalization to a single reference array.
  • the median-most array was selected based on autosomal intensities; then the correlation matrix was built for the adjacent 100
  • CNVs intersecting or overlapping T-ccll receptor regions (chr7:38,245J05-38,365/141; chr7: 141,647,285- 142,221,100; chr9:33,608,462-33,652,656; chrl4: 21,159,896-22,090,937) and abParts (chr2:88,937,989-89,411,302; chr2:88,966,183-89,377,035; chr2:89,589,457-89,897,555; chrl4: 105,065,301-106,352,275; chr22:20,715,572-21,595,082) were excluded.
  • CNVs ⁇ • .. ⁇ with median probe ratios (seg. median) between 0.83 and 1.15 were also removed as were CNVs smaller than 100 kb or larger than 10Mb.
  • CNV frequencies were determined in the combined set of cases and controls (separately within each ethnic group). CNV frequencies were estimated based on 50% reciprocal overlap between CNV calls of the same type. CNVs with frequency > 1% were removed.
  • association was quantified using the Exact Conditional test, with ancestry and study as covariates.
  • the segment with the lowest one-sided p-value was the peak of association within an ROI.
  • Absolute copy number (ACN) detection method by Sequenom MassArray combines real time competitive PCR (rPCR) with MassEXTEND procedures and matrix- assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF).
  • the CNV assay involves spiking genomic DNA template with genomic DNA from a single reference chimpanzee (Pan troglodytes) that was purchased from Southwest National Primate Research Center (San Antonio, Texas, USA).
  • the genotype assay targets a specific single nucleotide difference between human and chimpanzee, and relative copy number is determined based the ratio of peak areas of the human and chimp alleles.
  • Nucleotide differences between human and chimpanzee sequences were then categorized based on the position of difference in the alignment., alleles in human and chimpanzee, and .. direction of aligument. All aligned human-chimpanzee loci were processed to identify the location of any variant bases (single nucleotide polymorphisms and insertions/deletions) within a given distance of the specified human-chimpanzee loci. All known human and chimpanzee SNPs and indels were excluded in ( CNV assay design. Single base nucleotide extension (SBE) assays were then designed to target the non-conserved nucleotides using Sequenom Assay Design v3.1 software.
  • SBE Single base nucleotide extension
  • PCR was performed on Biorad thermocyclcrs in a 5 ⁇ reaction using 15ng of genomic human DNA (/wDNA). 15ng of P. troglodytes DNA (p/DNA), 0.5pmol of each primer in multiplex, 250 ⁇ dNTPs. 0.5 ⁇ 1 of 10X 20 mM MgCl PCR Buffer and 0.5units of Taq polymerase (Roche, USA). The PCR cycling parameters were 95°C for 15 min, followed by 45 cycles of 94°C for 30s, 56°C for 30s and 72°C for 1 min, followed by 72°C for 3 min. Following PCR, 5 ⁇ 1 PCR product was treated with 0.17 ⁇ 1 of 10X SAP .. (shrimp alkalinej>hosphate) buffer and 0.30 ⁇ 1 of SAP enzyme and incubated at 37°C for 40 min followed by heat denaturation of enzyme at 85°C for 5 min.
  • VIPR2 (05C43079 and 05C48386).
  • Subtelomeric probes were obtained for chromosome 7p and 7q (Abbott Molecular).
  • the genomic coordinates of the TelVysion 7q probe were Chr7: 158,551,912-158,650,925 (NCBI36/hgl8), which overlaps exons 1-4 of VIPR2. Hybridizations were performed according to manufacturer's protocols.
  • Sensitivity of CNV calls in the 7q36.3 region was examined to determine the possibility of a spurious association, which can arise, for instance, if there is a differential sensitivity to detect CNVs in control samples compared with the case samples.
  • Sensitivity of the segmentation-based CNV calling methods was evaluated by (a) :: examining CNVs within the 7q36.3 region after relaxing our stringent filtering criteria, and by comparing segmentation calls in cases and controls to CNV genotype calls made in the (b) 7q36.3 region and (c) elsewhere in the genome using targeted genotyping algorithms with enhanced sensitivity. These efforts were focused only on the microarray datasets that were processed for this study (the primary cohort and MGS subset in the secondary cohort). Published CNV call sets generated by the ISC study of schizophrenia have undergone evaluation in earlier studies i! . a) CNV segmentation calls in the 7q36.3 region examined using a lower sensitivity threshold
  • This improved signal can be accounted for by the smaller target region and reduced multiple testing correction.
  • the improved signal cannot be accounted for by the detection of additional small CNVs in cases, because only 3 smaller duplications overlapped the peak of association, one in cases and two in controls.
  • MeZOD Median Z-score Outlier Detection
  • Outlier detection-based methods 74 provide greater sensitivity for CNVs within defined target regions. If a significant number of CNVs overlapping the target region were undetected by the segmentation algorithms or filtered out of the call set, such variants can often be detected by MeZOD, leading to discordance between the segmentation calls and the MeZOD genotypes. When the distribution of z-scores for each target region was examined, punctate clusters of data points that are distinguishable from the overall distribution was observed.
  • Sensitivity at other loci throughout the genome was evaluated by examining sensitivity to detect a set of validated common CNPs (>100 kb in size) characterized as part of HapMap phase 3— .
  • Sensitivity to detect common CNPs by the segmentation algorithms is equivalent to that of rare CNVs (because parameters of HMM- , based segmentation algorithms arc not adjusted based on prior knowledge of common CNVs).
  • targeted genotyping methods have much greater sensitivity and accuracy. Therefore, concordance between the segmentation calls and a predefined set of common CNP genotypes were used as a measure of the segmentor sensitivity.
  • the primary dataset consisted of NimbleGen 2.1M array data.
  • the secondary dataset consisted of the MGS study (Affymetrix 6.0) and the ISC study of schizophrenia (which included data from Affymetrix 5.0 and 6.0 platforms). Combining data from multiple studies has the potential to create spurious associations. For instance, if data from two studies are combined and the study with the most sensitive platform had a large number of cases and a small number controls, a spurious enrichment of CNVs in cases could arise (if factors such as platform and study are not controlled for). There was no such a disparity in any of the 3 studies comprising our primary and secondary cohorts, which consisted of roughly equal numbers of cases and controls in each study.
  • Levels of VIPR2 mRNA were measured in lymphoblastoid cell lines obtained from the MGS study collection at the NIMH genetics repository, including patients with duplications and triplications of 7q36.3 and control individuals with normal diploid copy number of this region.
  • Cyclic AMP accumulation was measured in lymphoblastoid cell lines (0.5 million per ml) prc-incubatcd for 20 minutes with the cyclic nucleotide phosphodiesterase inhibitor isobutylmethylxanthine (IBMX, 200 ⁇ ), before the addition of the stimulatory agonists forskolin (10 ⁇ ) +/- VIP, [100 nM ], BAY 55-9837 (l OOnM) or prostaglandin E2 [PGE2, 1 ⁇ ] for 10 min. Reactions were terminated by pelleting the cells, aspiration - ⁇ ⁇ of the medium and addition of 100 ⁇ of cold 7.5% (wt/vol) trichloroacetic acid (TCA).
  • TCA cold 7.5%
  • Cyclic AMP content in TCA extracts was determined by radioimmunoassay and normalized to the number of cells per well. Data are expressed as cA P accumulation in response to the GPCR agonists relative to the response to non-GPCR agonist forskolin (10uM) and IBMX (200 mM) alone. Results presented for each subject represent the mean and standard error of at least ten replicates. Standard error and -values for pooled results were computed across individuals ( Figures lb-d).
  • Subject 02 ⁇ 0016 is male, age 44, of Norwegian descent. His diagnosis is schizoaffective disorder, depressed type, with onset at the age of 21. Family history: mother suffers from depression. Patient has never been married. He completed 4 years of college. He currently resides in a halfway house and attends a day treatment program. He is unemployed and receives disability. At age 16, he reported first feeling paranoid and having trouble in school. At age 21, he reported experiencing his first psychotic break and was hospitalized for 4 months. His symptoms primarily entailed paranoia. He also reported being depressed during his hospitalization. At age 22, he was hospitalized for a second time for suicidal thoughts, depression and feelings of .hopelessness.
  • P 7q36.3
  • Chr7: 158,448,321-158,810,016 duplications were detected in 29 of 8,290 (0.35%) patients and 2 of 7,431 (0.03%) controls in this study.
  • the p-valuc for the combined region in the combined sample was 5.7xl0 "7 and the OR was 14.1 [3.5. 123.9].
  • Inheritance of the duplication at 7q36.3 could be evaluated in three families.
  • family 02-135 the duplication was confirmed in the proband, but not detected in either of the unaffected parents, and thus is apparently de novo.
  • family 02-01 the duplication was detected in the proband and in a mother with a diagnosis of depression.
  • family LWJ02 the duplication was detected in the proband and in an unaffected mother.
  • the proband's mother also had a son with a diagnosis of schizophrenia (LW-102-03) from a second marriage, but DNA was not available on this individual.
  • Clinical psychiatric reports of patients 02-016 and 02-135 are provided below.
  • V1PR2 encodes the vasoactive intestinal peptide (VIP) receptor VPAC2, a G protein-coupled receptor that is expressed in a variety of tissues including, in the brain, the suprachiasmatic nucleus, hippocampus, amygdala, and hypothalamus— .
  • VIP vasoactive intestinal peptide
  • VPAC2 binds VIP— , activates cyclic- AMP signaling and PKA, regulates synaptic transmission in the hippocampus 13J& , and promotes the proliferation of neural progenitor cells in the dentate gyrus— .
  • VIP signaling plays a role in learning and memory— .
  • VPAC2 also plays a role in sustaining normal circadian oscillations in the SCN and VIPR2-nuil and VIPR2-overe. ⁇ pression 31 mice exhibit abnormal rhvthms of rest and activity.
  • VPC2R antagonists and agonists such as compounds I and 2 published by C et al. 2 ( Figure 3), and peptide derivatives of VIP published by Moreno ct al.— , such as selective antagonists, PG-96-238 and PG-96-465, and a partial agonist, PG-97-278 ( Figure 4), are also encompassed in the present invention for modulating VIPR2 expression and/or VPC2R activity, and subsequently for treating brain disorders.
  • V1PR2 transcription and cyclic-AMP signaling were ⁇ - significandy increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered VIP signaling in the pathogenesis of schizophrenia and suggest VIPR2 as a potential target for the development of novel antipsychotic drugs.
  • Vasoactive intestinal peptide acts via multiple signal pathways to regulate hippocampal NMD A receptors and svnaptic transmission. Hippocampus 19, 779-789 (2009).
  • the neurotransmitter VIP expands the pool of symmetrically dividing postnatal dentate gyrus precursors via VPAC2 receptors or directs them toward a neuronal fate via VPAC1 receptors. Stem Cells 27, 2539-25 1 (2009).
  • VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109, 497-508 (2002).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Analytical Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Immunology (AREA)
  • General Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Pathology (AREA)
  • Microbiology (AREA)
  • Vascular Medicine (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention concerne des compositions diagnostiques et thérapeutiques et des procédés de détection et de traitement de troubles neurologiques, comme la schizophrénie, l'autisme et d'autres troubles associés par la modulation de l'expression du gène de récepteur de peptide vasoactif intestinal 2 (VIPR2) ou la correction de mutations pathogènes du gène VIPR2, et par la modulation de l'activité du VIPR2 codant le récepteur de peptide vasoactif intestinal 2 (VPAC2R) dans la signalisation de cycHc-AMP avec des agonistes de VPAC2R sélectifs, des antagonistes de VPAC2R, et VIP ou ses dérivés ou analogues peptidiques.
PCT/US2012/023445 2011-02-01 2012-02-01 Diagnostic et traitement de troubles neurologiques par vipr2 et vpac2r Ceased WO2012106404A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161438453P 2011-02-01 2011-02-01
US61/438,453 2011-02-01

Publications (2)

Publication Number Publication Date
WO2012106404A2 true WO2012106404A2 (fr) 2012-08-09
WO2012106404A3 WO2012106404A3 (fr) 2012-11-01

Family

ID=46603282

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/023445 Ceased WO2012106404A2 (fr) 2011-02-01 2012-02-01 Diagnostic et traitement de troubles neurologiques par vipr2 et vpac2r

Country Status (1)

Country Link
WO (1) WO2012106404A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9701727B2 (en) 2011-06-29 2017-07-11 The Trustees Of Columbia University In The City Of New York Inhibitor of neuronal connectivity linked to schizophrenia susceptibility and cognitive dysfunction
WO2023278702A1 (fr) * 2021-06-30 2023-01-05 The Trustees Of Columbia University In The City Of New York Compositions et méthodes pour la prévention et le traitement de la peur induite par le stress, du comportement de type dépressif et de type anxiété

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060165679A1 (en) * 2002-05-08 2006-07-27 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with vasoactive intestinal peptide receptor 2 (vpac2)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9701727B2 (en) 2011-06-29 2017-07-11 The Trustees Of Columbia University In The City Of New York Inhibitor of neuronal connectivity linked to schizophrenia susceptibility and cognitive dysfunction
WO2023278702A1 (fr) * 2021-06-30 2023-01-05 The Trustees Of Columbia University In The City Of New York Compositions et méthodes pour la prévention et le traitement de la peur induite par le stress, du comportement de type dépressif et de type anxiété

Also Published As

Publication number Publication date
WO2012106404A3 (fr) 2012-11-01

Similar Documents

Publication Publication Date Title
US10228378B2 (en) Diagnostic and therapeutic methods and products related to anxiety disorders
US9702007B2 (en) Genetic markers predictive of response to glatiramer acetate
CA2907152A1 (fr) Proteines de fusion et procedes correspondants
US20230304094A1 (en) Genomic alterations associated with schizophrenia and methods of use thereof for the diagnosis and treatment of the same
TW201326399A (zh) 用於預測對格拉替雷（ｇｌａｔｉｒａｍｅｒ）醋酸鹽之臨床反應之單核苷酸多型性之判定
WO2007145992A2 (fr) Base génétique de la réponse au traitement chez des patients dépressifs
Pociot et al. TGF-beta1 gene mutations in insulin-dependent diabetes mellitus and diabetic nephropathy.
JP5191906B2 (ja) ヒトの記憶性能に影響を及ぼす遺伝子
JP6095889B2 (ja) 染色体２１ｑ、６ｑ、および１５ｑの遺伝子変異およびこれらを使用して１型糖尿病を診断および治療する方法
Alkelai et al. Identification of new schizophrenia susceptibility loci in an ethnically homogeneous, family‐based, Arab‐Israeli sample
JP2007503210A (ja) ヒト自閉症感受性遺伝子およびその使用
JP2007528707A (ja) 統合失調症の診断および治療のための標的としてのｅｇｒ遺伝子
US11655470B2 (en) Diagnosing COL6-related disorders and methods for treating same
WO2010111080A2 (fr) Traitement optimisé de la schizophrénie
WO2012106404A2 (fr) Diagnostic et traitement de troubles neurologiques par vipr2 et vpac2r
US20140171371A1 (en) Compositions And Methods For The Diagnosis of Schizophrenia
EP2992112B1 (fr) Mutations du gène pdgfrb et du gène notch3 responsables de la myofibromatose infantile autosomique dominante
US20160312284A1 (en) Select single nucleotide polymorphisms predictive of response to glatiramer acetate
WO2006097462A2 (fr) Compositions et methodes destinees a traiter des troubles du snc inflammatoires
JP2008525000A (ja) 統合失調症及び関連障害を治療するための組成物及び方法
US20220307085A1 (en) Method and Kit for Determining Neuromuscular Disease in Subject
WO2010022235A2 (fr) Une étude d'association à l'échelle du génome sur l'autisme révèle un nouveau locus à risque commun sur 5p14.1
Kwok An Investigation of Recent and Novel Genetic Variants that are Associated with the Pathogenesis of Amyotrophic Lateral Sclerosis and Their Implications on Phenotypes of the Disease
Kaufman Identification of Non-Syndromic Intellectual Disability Genes and Their Overlap with Autism
Zhang Genetic and functional analyses of diabetic nephropathy with focus on chromosome 3q

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12741897

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12741897

Country of ref document: EP

Kind code of ref document: A2