EP1014977A1 - Methodes de diagnostic de la migraine accompagnee d'aura, de depression et d'angoisse, a partir de variations alleliques de genes dopaminergiques - Google Patents

Methodes de diagnostic de la migraine accompagnee d'aura, de depression et d'angoisse, a partir de variations alleliques de genes dopaminergiques

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EP1014977A1
EP1014977A1 EP97938536A EP97938536A EP1014977A1 EP 1014977 A1 EP1014977 A1 EP 1014977A1 EP 97938536 A EP97938536 A EP 97938536A EP 97938536 A EP97938536 A EP 97938536A EP 1014977 A1 EP1014977 A1 EP 1014977A1
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drd2
alleles
migraine
syndrome
aura
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German (de)
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EP1014977A4 (fr
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Stephen J. Peroutka
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • C12Q2600/136—Screening for pharmacological compounds
    • 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
    • C12Q2600/172—Haplotypes

Definitions

  • the present invention relates generally to the diagnosis and treatment of a syndrome characterized by symptoms of migraine with aura, depression and/or anxiety.
  • Migraine headaches are a type of vascular headaches. Migraine headaches are characterized in part as recurrent attacks of headaches, with or without associated visual and gastrointestinal disturbances. Symptoms of migraine headaches usually follow a pattern in each patient. Attacks may be daily or only once in several months. Untreated attacks may last for hours or even days. Nausea, vomiting, photophobia and sonophobia are common. The extremities can become cold and cyanosed, and the patient can become irritable and seek seclusion. In the United States alone, approximately 18 million females and 5.7 million males have been estimated to suffer from severe migraine annually. Migraines are believed to be a leading cause of lost time ' from the workplace.
  • migraines A classification of migraines based on patient symptoms has been proposed by the Committee on the Classification of Headache of the International Headache Society, Cephalalgia 8:1-96 (1988). The committee proposes that migraines be classified a migraine without aura (formerly known as common migraine) , migraine with aura (formerly known as classic migraine) and hemiplegic migraine (formerly known as complicated migraine) . Migraine with aura and migraine without aura are the two most frequent forms of migraine.
  • a locus for familial hemiplegic migraine has been reported to occur on chromosome 19, Joutel et al . , Mature Genetics 5, 40-45 (1993); Joutel et al . , Am. J. Hum . Genet .
  • migraine is neither efficiently diagnosed nor managed (Cephalalgia 8, 96 (1988)). Similarities exist between the epidemiological characteristics of migraine, anxiety and depression (Robins et al., Arch. Gen . Psychiatry 41:949-958(1984); Stewart et al., JAMA 267:64-69 (1992); Rasmussen & Eisen, J Clin Psychiatry 55:5-14 (1994); Kessler et al., Arch. Gen .
  • the invention is directed to methods of diagnosing a patient for susceptibility to a syndrome characterized by symptoms of migraine with aura, depression and/or anxiety.
  • the methods entail detecting a variant allele of one or more dopaminergic genes in the patient.
  • Dopaminergic genes correlated with the syndrome include DRDl, DRD2 , DRD3 and DAT.
  • the presence of homozygous Al alleles of the DRD2 Ncol Al gene indicates increased susceptibility to the syndrome relative to the presence of heterozygous A1/A2 alleles
  • the presence of heterozygous A1/A2 alleles indicates increased susceptibility relative to the presence of ho ozygous A2/A2 alleles.
  • variant alleles are detected in two or more of the DRDl, DRD2 , DRD3 and DAT, and risk factors associated with the presence of each variant allele detected are combined to indicate susceptibility to the syndrome.
  • the invention further provides methods of treating a patient suffering from the syndrome described above.
  • the patient is administered a therapeutically effective amount of an agent that antagonizes binding of dopamine to DRDl, DRD2 , DRD3 and/or DAT.
  • Some such agents lack specific binding to DRD4 and/or DRD5.
  • Exemplary agents are shown in Table 1. Some agents are incapable of permeating the blood-brain barrier.
  • Agents can be administered intravenously, orally or intramuscularly.
  • Agents can be administered therapeutically or prophylactically. Patients amenable to treatment with such methods include those suffering from migraine with aura and having homozygous DRD2 Ncol Al alleles.
  • the invention provides methods of screening for a drug effective to treat the syndrome described above.
  • drugs are screened by determining their capacity to antagonize binding of dopamine to a dopaminergic receptor or DAT.
  • such drugs can be screened for lack of specific binding to DRD4 and/or DRD5.
  • the invention provides for the use of an agent that antagonizes binding of dopamine to DRDl, DRD2, DRD3 and/or DAT for the manufacture of a medicament for use in the treatment of a syndrome characterized by symptoms of migraine with aura, depression and/or anxiety in patients having a variant allele of one or more dopaminergic genes.
  • dopaminergic genes include DRDl, DRD2 , DRD3 and DAT.
  • suitable agents are listed in Table 1.
  • the blood-brain barrier is impermeable to passage of the agent.
  • Some agents antagonize DRDl, DRD2 , DRD3 and/or DAT without binding to DRD4 or DRD5.
  • the variant allele is DRD2 Ncol Al.
  • the presence of homozygous Al alleles indicates increased susceptibility to the syndrome relative to the presence of heterozygous A1/A2 alleles, and the presence of heterozygous A1/A2 alleles indicates increased susceptibility relative to the presence of homozygous A2/A2 alleles.
  • a patient having homozygous DRD2 Ncol Al alleles has a relatively high susceptibility to the syndrome.
  • the syndrome is manifested by symptoms of migraine with aura.
  • the medicament is administered intravenously, orally or intramuscularly. In some uses noted above, the medicament is administered prophylactically .
  • the invention provides methods for determining the suitability of a patient suffering from a syndrome characterized by symptoms of migraine with aura, depression and/or anxiety for treatment with an agent that antagonizes binding of dopamine to DRDl, DRD2, DRD3 and/or DAT.
  • the methods entail detecting a variant allele of one or more dopaminergic genes in the patient.
  • Some exemplary agents are listed in Table 1.
  • the blood-brain barrier is impermeable to passage of the agent.
  • Some agents antagonize DRDl, DRD2, DRD3 and/or DAT without binding to DRD4 or DRD5.
  • Such dopaminergic genes include DRDl, DRD2, DRD3 and DAT.
  • the variant allele is DRD2 Ncol Al and the presence of homozygous Al alleles indicates increased suitability relative to the presence of heterozygous A1/A2 alleles, and the presence of heterozygous A1/A2 alleles indicates increased susceptibility relative to the presence of homozygous A1/A2 alleles.
  • a patient having homozygous DRD2 Ncol Al alleles has a relatively high susceptibility to the syndrome.
  • the syndrome is manifested by symptoms of migraine with aura.
  • the agent is administered intravenously, orally or intramuscularly.
  • the invention further provides for use of an agent that antagonizes binding of dopamine to DRDl, DRD2 , DRD3 and/or DAT for the manufacture of a medicament for therapy.
  • a patient is diagnosed for susceptibility to a syndrome characterized by symptoms of migraine with aura, depression and/or anxiety by a method comprising the step of detecting a variant allele of one or more dopaminergic genes in the patient.
  • the one or more dopaminergic genes for which a variant allele is detected are selected from DRDl, DRD2 , DRD3 and/or DAT.
  • the variant allele is DRD2 Ncol Al and the presence of homozygous Al alleles indicates increased susceptibility to the syndrome relative to the presence of heterozygous A1/A2 alleles, and the presence of heterozygous A1/A2 alleles indicates increased susceptibility relative to the presence of homozygous A2/A2 alleles.
  • a patient having homozygous DRD2 Ncol Al alleles has a relatively high susceptibility to the syndrome.
  • the syndrome is manifested by symptoms of migraine with aura.
  • a therapeutically effective amount of an agent that antagonizes binding of dopamine to DRDl, DRD2 , DRD3 and/or DAT is then administered to the patient.
  • Some exemplary agents are listed in Table 1.
  • the blood-brain barrier is impermeable to passage of the agent.
  • Some agents antagonize DRDl, DRD2 , DRD3 and/or DAT without binding to DRD4 or DRD5
  • the agent is administered intravenously, orally or intramuscularly. In some uses, the agent is administered prophylactically.
  • the invention further provides diagnostic agents (e.g. , allele-specific probes and primers) , for detecting a variant allele of one or more dopaminergic genes for use in therapy, prophylaxis or diagnosis.
  • diagnostic agents e.g. , allele-specific probes and primers
  • dopaminergic genes can be selected from DRDl, DRD2 , DRD3 and DAT.
  • some diagnostic reagents are used to detect the Ncol Al allele of DRD2.
  • the invention further provides agents, such as any of those described above, for use in therapy, prophylaxis or diagnosis of a syndrome characterized by symptoms of migraine with aura, depression and/or anxiety.
  • the invention further provides for use of such agent in the therapy, prophylaxis or diagnosis of migraine with aura.
  • the invention further provides for the use of an agent for detecting a variant allele of one or more dopaminergic genes for the manufacture of a diagnostic for use in therapy, prophylaxis or diagnosis.
  • Preferred dopaminergic genes are selected from DRDl, DRD2 , DRD3 and DAT.
  • a suitable variant allele is DRD2 Ncol Al.
  • the diagnostic is typically used in the therapy, prophylaxis or diagnosis of a syndrome characterized by symptoms of migraine with aura, depression and/or anxiety. Further, the diagnostic can be used in the therapy, prophylaxis or diagnosis of migraine with aura.
  • the invention further provides for the use of an agent that antagonizes binding of dopamine to DRDl, DRD2 , DRD3 and/or DAT for the manufacture of a medicament for use in the treatment of a syndrome characterized by symptoms of migraine with aura, depression and/or anxiety associated with the presence of a variant allele of one or more dopaminergic genes.
  • a variant allele is present in one or more dopaminergic genes selected from DRDl, DRD2, DRD3 and DAT.
  • the variant allele is DRD2 Ncol Al and the presence of homozygous Al alleles indicates increased susceptibility to the syndrome relative to the presence of heterozygous A1/A2 alleles, and the presence of heterozygous A1/A2 alleles indicates increased susceptibility relative to the presence of homozygous A2/A2 alleles.
  • a patient having homozygous DRD2 Ncol Al alleles has a relatively high susceptibility to the syndrome.
  • the syndrome is manifested by symptoms of migraine with aura.
  • Some exemplary agents are listed in Table 1.
  • the blood-brain barrier is impermeable to passage of the agent.
  • Some agents antagonize DRDl, DRD2, DRD3 and/or DAT without binding to DRD4 or DRD5.
  • the agent is administered intravenously, orally or intramuscularly.
  • the agent is administered prophylactically.
  • BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A-1D show the percentage of individuals having migraine with aura for different DRDl, DRD2, DRD3 and DAT alleles.
  • Figure 2 shows a risk factor analysis of migraine with aura.
  • the present invention provides methods of diagnosing and treating a syndrome (mada) characterized by symptoms of, or susceptibility to, migraine with aura, depression and/or anxiety, and resulting, at least in part, from variation in one or more dopaminergic genes.
  • a syndrome characterized by symptoms of, or susceptibility to, migraine with aura, depression and/or anxiety
  • DRDl, DRD2 , DRD3 and DAT are associated with increased susceptibility to migraine with aura, depression and/or anxiety.
  • DRDl, DRD2 and DRD3 are three of five G proteincoupled receptors (DRD1-DRD5) for which dopamine appears to be the primary neurotransmitter . O'Dowd et al., "Dopamine Receptors," in Handbook of Receptors and Channels (ed.
  • DRDl is encoded by an intronless gene (Dearry et al . , Nature 347:72-76 (1990); Zhou et al . , Nature 347:76-80 (1990); Sunahara et al . , Nature 347:80-83 (1990)) and is expressed most abundantly in the caudate, nucleus accumbens and olfactory tubercle. DRDl receptors are thought to act as pre-synaptic autoreceptors modulating neurotransmitter release.
  • the DRD2 gene has a length of about 270 kb, including six introns, the first of which accounts for about 200 kb of the gene.
  • DRD2s are localized in numerous anatomical locations that are believed to play a major role in the pathogenesis of migraine. The highest density of DRD2s are in the substantia nigra and basal ganglia. In the substantia nigra, the DRD2s act as presynaptic autoreceptors which modulate dopamine release (Mengod et al . f Neurochem . Int . 20, 33S-43S (1992)).
  • dopamine receptors have been located directly in vascular beds (e.g. , on cerebral arteries) that are believed to be critical in the pathogenesis of migraine.
  • dopamine receptors have been localized to pial vessels (Oudart et al . , Arch . Int . Pharmacodyn . 252, 196-209 (1981); Edvinsson et al . , Br. J . Pharmac . 85, 403-410 (1985)) the site of neurogenic inflammation that is believed to play a major role in the headache component of migraine (Moskowitz, Trends Pharmacol . Sci . 13, 307-311 (1992)).
  • DRD2s are also located in the peripheral and/or central sympathetic nervous system.
  • DRD2s are also located on presynaptic noradrenergic sympathetic ganglia, where they act to inhibit the release from the sympathetic nerve terminals (Clark et al . , Acta Endocrine . , Suppl . 216 88, 75-81 (1978); Ziegler et al . , Clin . Pharmacol . Ther . 25, 137-142
  • the DRD3 gene has a high degree of sequence identity with the DRD2 gene (O'Dowd et al . , Handbook of Receptors and Channels : G Protein-coupled Receptors (ed Peroutka, S.J.) 95-123 (CRC Press, Boca Raton, 1994); Sokoloff et al . , Nature 347:146-151 (1990)).
  • the DRD3 receptor acts as both a postsynaptic receptor and an autoreceptor which inhibits dopamine release (Tang et al . , J . Pharmacol . Exp. Ther . 270:475-476 (1994)).
  • DRD3 has been localized to the limbic areas of the brain (Mengod et al . , Neurochem . Int . 20:33S-43S (1992); Sokoloff et al . , Nature 347:146-151 (1990)) suggesting that it may be associated with cognitive, emotional and endocrine functions. Most drugs that interact with DRD2 also interact with similar affinity with DRD3 (Sokoloff et al . , Nature 347:146-151 (1990)). However, the density of expressed DRD3 receptors is low, estimated at about 1% of that of DRD2 (Accili et al . , Proc . Nat . Acad . Sci . 93:1945-1949 (1996)).
  • the dopamine transporter (DAT) gene is a key regulatory protein in the dopamine pathway that modulates the amount of dopamine release and re-uptake (Shimada et al . , Science 254:576-577 (1991)).
  • Variant alleles of the dopaminergic genes DRDl, DRD2 , DRD3 and DAT probably cause increased susceptibility to migraine with aura, depression and/or anxiety as a result of increased dopaminergic transmission.
  • the proposed role of dopaminergic genes in migraine with aura is consistent with several clinical features of the disease. For example, nausea and/or vomiting are common features of migraine in which dopamine stimulation is likely. Gastrokinetic changes, hypotension and other autonomic nervous system changes are additional migraine symptoms that are consistent with disturbances in dopaminergic neurotransmission.
  • the proposed mechanism is also consistent with previous reports of exaggerated autonomic responses to dopamine agonists in migraine patients. For example, apo orphine has been reported to induce symptoms of migraine, as well as the associated phenomenon of nausea, vomiting, yawning, hypotension and syncope (DelZompo et al., Headache 35, 222-224 (1995)).
  • the methods of diagnosis and treatment described below usually require knowledge of the genotype of an individual with respect to polymorphisms in the genes DRDl, DRD2, DRD3 , and/or DAT.
  • Exemplary polymorphisms within each of these genes that correlate with migraine with aura, depression and/or anxiety are described in the Examples, as are methods for their detection.
  • these polymorphisms include: an A to G polymorphism in the 5' untranslated region of DRDl having alleles designated Bl and B2 as described by Cichon et al . , Hum . Hoi . Genet .
  • DRD2 TaqI Al allele Noble, Science & Hedicine 3, 52-61 (1996)
  • DRD2 Ncol Al can be used in diagnostic methods in a similar manner to DRD2 Ncol Al.
  • DRDl, DRD2 , DRD3 and DAT genes that correlate with migraine with aura, anxiety and/or depression can be identified as follows.
  • the first step is to identify additional polymorphic sites within one of these genes.
  • polymorphic sites can be identified either by comparative sequencing of these genes in a population of individuals or from the published literature and databases.
  • additional polymorphic sites in the DRD2 gene have been published including TaqlB within intron 2, Fokl B at position 1105, HphI at position 3208, C311S at position 3413, Ncol at position 3420 and TaqlA within the 3' untranslated region.
  • a correlation is performed between type of polymorphic form and presence or absence of migraine with aura, depression, and/or anxiety in a population.
  • the correlation can be determined with respect to combinations of two or more polymorphisms within the same gene.
  • individuals having the Ncol Al allele are subdivided into two classes respectively having Al and A2 alleles of the Fokl polymorphism.
  • Variant genes can be detected, for example, by sequencing, allele-specific amplification (Gibbs, Nucleic Acid Res . 17, 12427-12448 (1989)), restriction enzyme analysis, allele-specific probe hybridization assays (Saiki et al., Nature 324, 163-166 (1986)) or singlestranded conformational analysis (Orita et al., Proc. Natl . Acad . Sci . 86, 2766-2770 (1989)).
  • the Ncol Al and A2 alleles can be distinguished by Ncol digestion. Only the A2 allele is cut.
  • Reagents used for detecting variant alleles, such as allele specific probes and primers can be packaged as diagnostic reagents. The diagnostic reagents can bear labels indicating their suitability for use in diagnosis of the mada syndrome or a symptom thereof.
  • DRD2, DRD3 and/or DAT gene in a patient can be used as a measure of susceptibility to migraine with aura, depression and/or anxiety.
  • detection of one or both copies of the Ncol Al allele of DRD2 indicates increased susceptibility to migraine with aura, depression and/or anxiety in the patient, and detection of both copies indicates increased susceptibility relative to one copy.
  • Detection of one or both copies of DRDl Bl indicates increased risk of migraine with aura relative to homozygous DRDl B2.
  • Detection of homozygous DRD3 A2 indicates increased risk of migraine with aura relative to homozygous or heterozygous DRD3 Al.
  • Detection of homozygous DAT 10 indicates increased risk of migraine with aura relative to heterozygous DAT 10/9 and probably 9/9 genotype, although the latter occurs with insufficient frequency to have been included in the present analysis.
  • each variant allele associated with the mada syndrome can be assigned a risk factor related to the probability, as discussed in the Examples.
  • Fig. 2 shows the percentage of individuals having migraine with aura as a function of number of risk factors present. It can be seen that no individuals without any dopaminergic risk factor have symptoms of the mada syndrome and about 75% of individuals with all five dopaminergic risk factors have symptoms of the mada syndrome. Individuals with 1-4 risk factors show intermediate frequencies of symptoms of the mada syndrome in relation to the number of risk factors present.
  • There are probably other genes besides the dopaminergic genes described above having variant forms associated with risk of the mada syndrome The existence of variant forms of such genes can be detected and correlated with probabilities of susceptibility to the syndrome in similar fashion to the analysis of dopaminergic genes. Combined statistical analysis of dopaminergic genes with other genes still further increases the predictive value of the diagnosis.
  • the analysis is useful in identifying a subset of patients having a common genetic basis giving rise to the mada syndrome. Such patients are amenable to treatment with antagonists of dopaminergic genes as discussed below. Treatment with such antagonists may be ineffective in other patients, who exhibit similar symptoms to patients with the syndrome, but due to a different genetic basis. This analysis is also useful in distinguishing migraine with aura from migraine without aura, and others diseases, such as stroke, which may present with similar symptoms. That is, a patient with a high number of risk factors for the mada syndrome is more at risk for migraine with aura than for migraine without aura or stroke. IV. Methods of Treatment
  • the invention further provides methods of treating patients suffering from, or susceptible to, the mada syndrome.
  • a patient having or susceptible to symptoms of migraine with aura, depression and or anxiety is treated with a therapeutically effective dose of an antagonist to one or more of the dopaminergic genes DRDl, DRD2 , DRD3 and DAT.
  • Such a dose is sufficient to prevent, arrest or detectably relieve symptoms of migraine with aura, depression and/or anxiety.
  • the dose can be administered prophylactically or therapeutically.
  • the dose can also be administered to pediatric or handicapped patients but who are unable to articulate their symptoms but are known to have variant forms of one or more variant forms of the dopaminergic genes associated with the disease.
  • DRD2 antagonists include phenothiazines (chlorpromazine, fluphenazine, prochlorperazine, promethazine, thioridazine and trifluoperazine) , butyrophenomes (droperidol, haloperidol, pimozide, spiperone) , thioxanthines (chlorprothixene, thiothixene) and other drugs, such as clozapine.
  • phenothiazines chlorpromazine, fluphenazine, prochlorperazine, promethazine, thioridazine and trifluoperazine
  • butyrophenomes droperidol, haloperidol, pimozide, spiperone
  • thioxanthines chlorprothixene, thiothixene
  • other drugs such as clozapine.
  • Some antagonists are capable of crossing the blood-brain barrier and therefore capable of antagonizing both central and peripheral dopaminergic receptors.
  • Other antagonists such as domperidone do not cross the blood-brain barrier and therefore antagonize only peripheral receptors.
  • Some agents such as domperidone, metoclopramide, chlorpromazine, prochloperazine and flunarazine have previously been reported to have some value in treating some migraine patients. However, the mechanism of action was not known, not was it appreciated that the agents are most appropriate for administration to the subset of migraine patients having migraine with aura and variant forms of one or more of the dopaminergic genes DRDl, DRD2 , DRD3 , DRD4 and DAT.
  • Antagonists can be used to manufacture medicaments for use in treatment of the syndrome.
  • Antagonists can be mixed with a pharmaceutical carrier, which can be any compatible, non-toxic substance suitable to deliver the antagonist to the patient.
  • a pharmaceutical carrier can be any compatible, non-toxic substance suitable to deliver the antagonist to the patient.
  • Sterile water, alcohol, fats, waxes, and inert solids can be used as the carrier.
  • Pharmaceutically-acceptable adjuvants, buffering agents, dispersing agents, and the like can also be incorporated into the pharmaceutical compositions.
  • concentration of the active agent in the pharmaceutical composition can vary widely, i.e., from less than about 0.1% by weight, usually being at least about 1% by weight to as much as 20% by weight or more.
  • Medicaments can be administered intravenously, intramuscularly, subcutaneously, intranasally, cutaneously, via suppository, by inhalation or orally.
  • Methods for preparing parenterally administrable compositions are described in more detail in, for example, Remington ' s Pharmaceutical Science (15th ed. , Mack Publishing Company, Easton, Pennsylvania, 1980) (incorporated by reference in its entirety for all purposes) .
  • the active ingredient can be administered in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions.
  • Active component (s) can be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate and the like.
  • inactive ingredients examples include red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, edible white ink and the like.
  • Similar diluents can be used to make compressed tablets . Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • the invention further provides methods of screening for novel antagonists of DRDl, DRD2 , DRD3 and/or DAT for treatment of the syndrome.
  • Potential agents are screened for specific binding (Kd ⁇ ⁇ M) to human DRDl, DRD2 , DRD3 or DAT, optionally in competition with dopamine.
  • Preferred agents bind with a Kd less than 10 nM and can therefore usually be used at a dose of about 10 mg/patient.
  • Receptor binding assays can be performed as described by Ison & Peroutka, Cancer Treatment Reports 70, 637 (1986); Peroutka & Snyder, Am . J .
  • Some agents are screened for lack of specific binding to at least one of dopaminergic receptors DRD4 or DRD5.
  • the agents can also be screened for lack of specific binding to other receptors to minimize side effects. For example, lack of binding to the -adrenergic receptor minimizes orthostatic hypotensive side-effects.
  • Preferred agents have a serum half-life of about 24 hr and can reach peak plasma levels within about 15-60 min of administration.
  • This example describes analysis of allelic variants within all five dopamine receptor genes (DRDl, DRD2, DRD3, DRD4 and DRD5) and the DAT gene in control, migraine without aura (MO) and MWA individuals.
  • Subjects were identified for this study by physician referral. Individuals were evaluated using the diagnostic criteria for MO and MWA established by the International Headache Society (Cephalalgia 8, 1-96 (1988)). The lifetime presence or absence was determined for each of the criteria in the IHS definition of migraine. Interviews were conducted by physicians, nurses and/or trained interviewers. All interviewers were trained by the present inventor in the use of the IHS criteria and all clinical data were reviewed by the same neurologist. Control group individuals did not meet IHS criteria for migraine (based on direct interview) and were predominantly unaffected spouses of the individuals with migraine. Informed consent was obtained and DNA samples collected. All clinical data were obtained independently of the genotypic data. The average age of the study participants is 53 ⁇ 1 years. No variation was observed between the 3 study groups in terms of age, sex or ethnic origin.
  • Genotypin A total of 246 DNA samples from unrelated individuals, who were 35 years of age or older, were analyzed (115 control individuals; 77 MO individuals; 54 MWA individuals) . Genomic DNA was isolated using the Puregene DNA isolation kit (Gentra Systems, Research Triangle Park, North Carolina) . Genotypes were scored independently by two individuals blinded to the clinical status. 3. DRDl . DRD2 , DRD3 anc? DRD5 DRDl, DRD2, DRD3 and DRD5 were amplified as follows. Briefly, 40 ng of genomic DNA was amplified in 10 ⁇ L of a solution containing lx Perkin Elmer PCR amplification buffer, 400 ⁇ M each dNTP, 0.5 U TagrGold polymerase
  • the enzyme was activated with an initial incubation at 94°C for 10 minutes, followed by 14 cycles of amplification with denaturation at 94°C for 20 seconds, annealing at 63°C for 1 minute, elongation at 72°C for 30 seconds with a decrease of 0.5°C and 3 seconds for each annealing step, and an additional 40 cycles of denaturation at 94°C for 30 seconds, annealing at 56°C for 30 seconds and elongation at 72°C for 1 minute.
  • DRD4 genotypes were assessed by amplifying 50 ng of genomic DNA in 10 ⁇ L of lx ThermoPol buffer (New England Biolabs) , 400 uM dNTP, 1 uM of each primer (see Table 2) and 0.2 U Vent (exo " ) Polymerase. Amplification consisted of 35 cycles of denaturation at 98 °C for l minute and annealing/elongation at 70 °C for 5 minutes. Amplification products were analyzed on 1.2% agarose gels.
  • DAT DAT genotypes were assessed by amplifying 40 ng of genomic DNA in the presence of 0.5 ⁇ M of fluorescence- labelled dUTP (Applied Biosystems, Foster City, CA) . Reactions progressed through 35 cycles of denaturation at 94 °C for 1 minute and annealing/elongation at 72 °C for 1 minute. Amplified products were analyzed on an ABI 373 sequencer using a 6% polyacrylamide gel. Analysis was performed as described previously (Vandenbergh et al . , Hoi . Brain Res . 15, 161-166 (1992)); Doucette-Stamm et al. Genet . Epidemiol . 12, 303-308 (1995)).
  • DRDl 5' UTR B and B2 Allele Frequencies An A to G polymorphism has been described in the 5 ' untranslated region of the DRDl gene (Cichon et al., Hum . Hoi . Genet . 3, 209-209 (1994)).
  • n 246 individuals
  • the DRDl Bl allele frequency is 0.37
  • the B2 allele frequency is 0.63.
  • DRD2 iVcoI Al and A2 Allele Frequencies A C to T polymorphism, resulting in a silent mutation at amino acid 313, has been described in the DRD2 gene (Sarkar et al . , Genomics 11, 8-14 (1991).).
  • the DRD2 Ncol Al allele frequency is 0.73
  • the A2 allele frequency is 0.27.
  • the DRD2 Ncol A allele frequencies were also determined in each subgroup of subjects (Table 5) . Similar allele frequencies were observed in both the control group and individuals with MO. By contrast, individuals with migraine with aura had a significantly greater frequency of the DRD2 Al allele (0.83) than either the control group or individuals with migraine without aura.
  • a polymorphism resulting in a glycine to serine substitution at position 9 in the ⁇ -terminal part of the DRD3 receptor was analyzed (Lannfelt et al . , Psychiatr. Genet . 2 , 249-256 (1992)).
  • the polymorphism consists of a A to G substitution which is 25 bp downstream from the start codon, creating a restriction site for Ball. This polymorphism has been hypothesized to play a role in receptor insertion into the cell membrane (Rietschel et al . , Psychiatr. Res . 46, 253-259 (1993).
  • the DRD3 Al allele frequency is 0.62 and the A2 allele frequency is 0.37. These values are similar to the DRD3 allele frequencies reported in previous studies (id.).
  • 37% of individuals have the Al/Al genotype, 50% have the A1/A2 genotype and 12% display the A2/A2 genotype.
  • A1/A1 (%) A1/ ⁇ 2 (%> A2/A2 (%l Al A2
  • D D4 Allele Frequencies The DRD4 gene contains a 48-bp sequence in the third cytoplasmic loop of the receptor that ranges from 2- to 8-fold repeat units (Van Tol et al . , Nature 358, 149-152 (1992) .
  • genotypes were obtained on 238 of the 246 individuals.
  • 106 individuals 45%
  • display the most common genotype i.e., 4/4) whereas 91 individuals (38%) have at least one 7 allele (Table 6).
  • the DRD5 Al allele frequency is 0.68 and the A2 allele frequency is 0.32. These values are similar to the DRD5 allele frequencies reported in the North American population (So meret al., Hum . Genet . 92, 633-634 (1993)).
  • the overall dataset 47% of individuals have the Al/Al genotype, 43% have the A1/A2 genotype and 10% display the A2/A2 genotype.
  • No significant difference was observed in the genotypic distribution between the control group, individuals with MO and individuals with MWA (Table 7) .
  • MWA is observed in 22% of the Al/Al individuals, 23% of the A1/A2 individuals and 16% of the A2/A2 individuals. Similar allele frequencies are observed in the control group, individuals with MO and individuals with MWA (Table 7) .
  • allelic "risk factors” were identified that were associated independently with an increased susceptibility to MWA compared to alternative genotypes at the same molecular location within the dopaminergic genes: the DRDl Bl/Bl or B1/B2 genotype, the DRD2 Al/Al genotype, the DRD2 A1/A2 genotype, the DRD3 A2/A2 genotype and the DAT 10/10 genotype.
  • the strength of the associations varied amongst the different genes, an initial attempt to develop a "risk factor" profile for MWA assigned equal weight to each allelic "risk factor” with a single exception: the DRD2 Al allele.
  • Individuals with the DRD2 Al/Al genotype were assigned a risk factor of "2" since the frequency of MWA appeared to be related to the number DRD2 Al alleles present in an individual (Table
  • allelic "risk factors” were determined for each individual in the present study (i.e., 0-5 dopaminergic allelic "risk factors” per individual) .
  • the frequency of MWA was then determined in each allelic "risk factor” group.
  • the data described in this study are derived from a clinical genetic relational database that was developed initially for the genetic analysis of migraine Peroutka & Howell, Towards Higraine 2000 , (Amsterdam, Elsevier Science B.V. , 1996), pp. 35-48. Potential subjects were identified by physician or self-referral. Subjects were evaluated using a semi-structured interview for migraine. Migraine evaluations were conducted by a neurologist and/or trained interviewer. The lifetime presence or absence was determined for each of the criteria in the International Headache Society (IHS) definition of migraine with (MWA) (Cephalalgia 8, 1-96 (1988) .
  • IHS International Headache Society
  • DSM-III-R Structured Clinical Interview for DSM-III-R
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders-IV
  • DSM-IV Diagnostic and Statistical Hanual of Hental Disorders . Vol. 4. (Washington, DC, American Psychiatric Association, 1994) , pp. pp. 317-391 and 393-444) was used to evaluate anxiety and depressive disorders in the same individuals interviewed for migraine.
  • the interview included questions that were appropriate to establish a DSM-IV-based diagnosis of generalized anxiety disorder (GAD) , phobias, panic attacks, panic disorder, obsessive-compulsive disorder (OCD) and major depression.
  • GAD generalized anxiety disorder
  • OCD obsessive-compulsive disorder
  • Interviews were performed by physicians or trained psychiatric nurses. Diagnoses required the concurrence of at least 3 physicians.
  • Genomic DNA was isolated using the Puregene DNA isolation kit (Gentra Systems, Research Triangle Park, North Carolina) . Genotyping of the DRD2 Ncol polymorphism was performed using previously described primers (Sarkar et al., Genomics 11,8-14 (1991). Briefly, 40 ng of genomic DNA was amplified in 10 uL of a solution containing lx Perkin Elmer PCR amplification buffer, 400 uM each dNTP, 0.5 U TagGold polymerase
  • the clinical diagnoses were based on DSM criteria for the anxiety disorders and major depression and on IHS criteria for MWA. If a clear diagnosis could not be made, the individual was "not diagnosed” and was not included in further statistical analyses for the disorder.
  • the incidences of the various clinical diagnoses based on DRD2 Ncol genotypes is provided in Table 10.
  • a present or past history of MWA, anxiety disorders or major depression is present in 69% of the Al/Al individuals, 53% of the A1/A2 individuals and 22% of the A2/A2 individuals.
  • Obsessive ComDulslv ⁇ Disorder 14% 16% 0% 0.01 n.s.
  • Major depression, panic attacks, MWA and phobia are also all increased significantly in the Al/Al vs. A2/any individuals (Table 10) .
  • both panic disorder and OCD are more frequent in the Al/Al vs. A2/any individuals, the difference does nor reach statistical significance.
  • the present data indicate that MWA, anxiety disorders and major depression are comorbidly associated with allelic variations in the DRD2 gene. As a result, some manifestations of these diseases may constitute a distinct clinical syndrome resulting from a single underlying genetic variation. The clinical recognition that all three disorders are associated with the same genetic variant has significant diagnostic and therapeutic implications.
  • NNC-22-0031 preclinical psychosis 5-HT3 ant Novo Nordisk A S alpha 1 ant

Abstract

L'invention concerne des méthodes de diagnostic d'un syndrome caractérisé par des symptômes de migraine accompagnée d'aura, de dépression et/ou d'angoisse. Le diagnostic consiste à détecter un allèle d'au moins un gène dopaminergique, par ex. DRD1, DRD2, DRD3 et DAT. L'invention concerne également des méthodes de criblage d'agents thérapeutiques servant à traiter ledit syndrome, ainsi que des méthodes de traitement correspondantes.
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