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Methods and compositions for the treatment of psychotic disorders through the identification of the sult4a1-1 haplotype

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Methods and compositions for the treatment of psychotic disorders through the identification of the sult4a1-1 haplotype


Methods and compositions that relate to genetic markers of psychotic disorders, e.g., schizophrenia (SZ), are provided. For example, in certain aspects methods for determinations of a SULT4A1-1 haplotype are described. Furthermore, the invention provides methods and compositions involving treatment of psychotic disorders using the haplotype status.
Related Terms: Psychotic Disorders Schizophrenia

Browse recent Suregene LLC patents - Jeffersontown, KY, US
Inventors: Timothy L. Ramsey, Mark D. Brennan
USPTO Applicaton #: #20120277211 - Class: 51421113 (USPTO) - 11/01/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai >Hetero Ring Contains Seven Members Including Nitrogen, Carbon And Chalcogen >Polycyclo Ring System Which Contains The Seven-membered Hetero Ring As One Of The Cyclos >Tricyclo Ring System Having The Seven-mmbered Hetero Ring As One Of The Cyclos >Nitrogen Bonded Directly To Ring Carbon Of The Seven-membered Hetero Ring



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The Patent Description & Claims data below is from USPTO Patent Application 20120277211, Methods and compositions for the treatment of psychotic disorders through the identification of the sult4a1-1 haplotype.

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CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. application Ser. No. 12/939,049 filed Nov. 2, 2010, which is a continuation-in-part of co-pending U.S. application Ser. No. 12/859,056, filed Aug. 18, 2010, and co-pending U.S. application Ser. No. 12/858,917, filed Aug. 18, 2010, each of which is a continuation-in-part of U.S. application Ser. No. 12/646,723, filed Dec. 23, 2009, now issued as U.S. Pat. No. 7,790,396, and co-pending U.S. application Ser. No. 12/612,438, filed Nov. 4, 2009. The entire contents of each of the referenced applications are incorporated herein by reference.

This invention was made with government support under SBIR grant MH078347 and grants NOl MH900001 and MH074027 awarded by National Institutes of Mental Health. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the field of psychotic disorders, such as schizophrenia and bipolar disorders. More particularly, it concerns genetic markers of antipsychotic response, for example, genes and genetic markers that influence or predict a person's likely response to antipsychotic medications.

2. Description of Related Art

Numerous drugs exist to treat psychotic disorders, such as schizophrenia (SZ), related SZ-spectrum disorders (including schizotypal personality disorder (SPD) and schizoaffective disorder (SD)), and bipolar disorders (BD). Most of these drugs fall into one of two categories, typical (first generation) and atypical (second generation).

Although head to head studies of large groups of patients, either in the acute phase or outpatient treatment, show that most atypical antipsychotic drugs are equally efficacious for positive symptoms, there are individual differences in response to specific drugs based on differences in drug pharmacology and metabolism, combined with genetic differences between patients. There are currently no proven ways to identify which antipsychotic drug is optimal for a given patient. Thus, patients switch from one drug to another when response is not considered to be adequate or side effects are intolerable. This switching of medication incurs a variety of increased costs, both economic and patient and caregiver hardship. On average, each patient may change medications three times before finding one that works. Additionally, the current drugs have significant side-effects. This combination of side-effects and limited efficacy create a vast unmet need for selecting the optimal antipsychotic for each patient.

Moreover, the limited or partial response that is often seen with antipsychotics leads to polypharmacy, where physicians prescribe two or more antipsychotic drugs plus mood stabilizers and/or antidepressants. Polypharmacy increases medication costs and significantly increases the likelihood of adverse advents and drug interactions (Stahl and Grady, 2006).

Pharmacogenomics, using genetic variation to predict altered response and side-effects profiles, will be important for enhanced patient care going forward. There continues to exist, therefore, a need to identify specific genetic variations that are associated with treatment outcomes for psychotic disorders.

SUMMARY

OF THE INVENTION

The invention is in part based on the finding that a particular haplotype, which the inventors refer to as the SULT4A1-1 haplotype, is a biomarker that can be used for selecting a more appropriate antipsychotic treatment plan for a particular subject. For example, the inventors have discovered that patients that have a SULT4A1-1 haplotype respond better when treated with olanzapine than SULT4A1-1 positive patients treated with risperidone, and respond better than SULT4A1-1 negative patients treated with olanzapine. Similarly, the inventors have discovered that patients that have a SULT4A1-1 haplotype respond better when treated with quetiapine than SULT4A1-1 negative patients treated with quetiapine. Further, the inventors have discovered that patients that do not have a SULT4A1-1 haplotype respond better when treated with risperidone than SULT4A1-1 positive patients treated with risperidone. Thus, prior determination of a patient's SULT4A1-1 haplotype status can aid in the development of an optimal antipsychotic treatment regimen.

Thus, an aspect of the invention involves determining whether genetic material of the subject comprises a SULT4A1-1 haplotype. Of course, to meet the need to transfer and store genetic information, the results of the determination will preferably be recorded and maintained in a tangible medium, such as a computer-readable disk, a solid state memory device, an optical storage device or the like, more specifically, a storage device such as a hard drive, a Compact Disk (CD) drive, a floppy disk drive, a tape drive, a random access memory (RAM), etc.

One preferred manner of obtaining the genetic haplotype information involves analyzing the genetic material of the subject to determine the presence or absence of the SULT4A1-1 haplotype. This can be accomplished, for example, by testing the subject's genetic material through the use of a biological sample. In certain embodiments, the methods set forth will thus involve obtaining a biological sample from the subject and testing the biological sample to identify whether a SULT4A1-1 haplotype is present. The biological sample may be any biological material that contains DNA or RNA of the subject, such as a nucleated cell source. Non-limiting examples of cell sources available in clinical practice include hair, skin, nucleated blood cells, buccal cells, any cells present in tissue obtained by biopsy or any other cell collection method. The biological sample may also be obtained from body fluids, including without limitation blood, saliva, sweat, urine, amniotic fluid (the fluid that surrounds a fetus during pregnancy), cerebrospinal fluid, feces, and tissue exudates. DNA may be extracted from the biologic sample such as the cell source or body fluid using any of the numerous methods that are standard in the art.

In some embodiments, an in vitro method for obtaining genetic information about a test subject is provided. The test subject may be a subject that is undergoing or is to undergo antipsychotic pharmacotherapy. For example, the test subject may be undergoing or is to undergo antipsychotic treatment with olanzapine, risperidone, quetiapine, or perphenazine. The in vitro method may comprise determining whether the genetic material in a biological sample comprises a SULT4A1-1 haplotype, wherein the SULT4A1-1 haplotype is defined as a haplotype comprising rs763120(C), a combination of rs2285162(A)-rs2285167(G), or a combination of rs2285166(T)-rs2285167(G), to thereby obtain the genetic information. Such a method may further comprise extracting DNA from a biological sample, and the genetic material may be analyzed by SNP genotyping or sequencing. In some aspects, the methods provided further comprise recording the genetic information that is determined in a tangible medium, such as, for example, a computer-readable disk, a solid state memory device, or an optical storage device. In other aspects, the methods provided further comprise reporting the determination to the subject, a health care payer, a physician, a pharmacist, a pharmacy benefits manager, or an electronic system. In certain embodiments, the determining step is carried out through the use of an array or a kit comprising a plurality of primers or probes specific for a SULT4A1-1 haplotype, wherein the SULT4A1-1 haplotype is defined as a haplotype comprising rs763120(C), a combination of rs2285162(A)-rs2285167(G) or a combination of rs2285166(T)-rs2285167(G).

Determining whether the genetic material exhibits a SULT4A1-1 haplotype polymorphism can be by any method known to those of ordinary skill in the art, such as genotyping (e.g., SNP genotyping) or sequencing. Techniques that may be involved in this determination are well-known to those of ordinary skill in the art. Examples of such techniques include allele specific oligonucleotide hybridization, size analysis, sequencing, hybridization, 5′ nuclease digestion, single-stranded conformation polymorphism analysis, allele specific hybridization, primer specific extension, and oligonucleotide ligation assays. Additional information regarding these techniques is discussed in the specification below.

For haplotype determinations, the sequence of the extracted nucleic acid of the subject may be determined by any means known in the art, including but not limited to direct sequencing, hybridization with allele-specific oligonucleotides, allele-specific PCR, ligase-PCR, HOT cleavage, denaturing gradient gel electrophoresis (DDGE), and single-stranded conformational polymorphism (SSCP) analysis. Direct sequencing may be accomplished by any method, including without limitation chemical sequencing, using the Maxam-Gilbert method, by enzymatic sequencing, using the Sanger method, mass spectrometry sequencing, and sequencing using a chip-based technology. In particular embodiments, DNA from a subject is first subjected to amplification by polymerase chain reaction (PCR) using specific amplification primers. In some embodiments, the method further involves amplification of a nucleic acid from the biological sample. The amplification may or may not involve PCR. In some embodiments, the primers are located on a chip.

In specific embodiments, the subject is a human. For example, in some embodiments the human is a subject who has, is suspected to have, or is at risk of a psychotic disorder, such as schizophrenia, schizotypal personality disorder (SPD), schizoaffective disorder (SD), or bipolar disorder (BD). In one embodiment, the subject is a patient having previously diagnosed a psychotic disorder (e.g., a patient suffering from early, intermediate or aggressive psychotic disorder). In some embodiments, the subject is of Caucasian (CA) descent, i.e., has one or more ancestors who are CA.

Moreover, the inventors contemplate that the genetic structure and sequence, including SNP profiles, of individual subjects will at some point be widely or generally available, or will have been developed by an unrelated third party. In such instances, there will be no need to test or analyze the subject's biological material again. Instead, the genetic information will in such cases be obtained simply by analyzing the sequencing or genotyping outcome of the subject, for example, a SNP profile, a whole or partial genome sequence, etc. These outcome can then be obtained from or reported by a sequencing or a genotyping service, a laboratory, a scientist, or any genetic test platforms.

In some further aspects, the method may further comprise reporting the determination to the subject, a health care payer, an attending clinician, a pharmacist, a pharmacy benefits manager, or any person that the determination may be of interest.

In certain embodiments, there is also provided a method of developing a pharmacotherapeutic treatment plan for a subject having or suspected of having a psychotic disorder comprising determining the SULT4A1-1 haplotype status of the patient, wherein a) if the subject comprises a SULT4A1-1 haplotype, the subject is more likely to exhibit a favorable response to olanzapine; and b) if the subject does not comprise a SULT4A1-1 haplotype, the subject is less likely to exhibit a favorable response to olanzapine; and developing the pharmacotherapeutic treatment plan. For example, if the subject comprises a

SULT4A1-1 haplotype, then the method may further comprise treating the subject with olanzapine. If the subject does not comprise the SULT4A1-1 haplotype, then the method may further comprise treating the subject with an antipsychotic treatment other than olanzapine, such as treating with risperidone, or perphenazine.

In certain embodiments, there is also provided a method of determining elevated risk of a patient to discontinue treatment with olanzapine due to a treatment-emergent adverse event, comprising determining the SULT4A1-1 haplotype in a patient sample, wherein a) if the human subject comprises the SULT4A1-1 haplotype, the subject is more likely to exhibit a propensity to continue treatment; and b) if the subject does not comprise the SUTL4A1-1 haplotype, the subject is more likely to exhibit a propensity to discontinue treatment due to a treatment-emergent adverse event. Steps for determining the SULT4A1-1 haplotype and determining the propensity of the subject to continue or discontinue treatment may be carried out in vitro.

In certain embodiments, there is also provided a method of selecting a pharmacotherapeutic treatment plan for a human subject having the potential to experience a treatment-emergent adverse event when treated with olanzapine, comprising determining the

SULT4A1-1 haplotype in a sample, wherein a) if the human subject does not comprise the SULT4A1-1 haplotype the subject is more likely to experience a treatment-emergent adverse event when treated with olanzapine; and b) if the subject comprises the SUTL4A1-1 haplotype the subject is not more likely to experience a treatment-emergent adverse event when treated with olanzapine; selecting a pharmacotherapeutic treatment plan based on the SULT4A1-1 haplotype; and treating the subject with the selected pharmacotherapeutic treatment. For example, the pharmacotherapeutic selected may be olanzapine or a non-olanzapine antipsychotic treatment, such as risperidone, quetiapine, ziprasidone, or perphenazine. In some embodiments, the subject comprises the SULT4A1-1 haplotype, and the pharmacotherapeutic is olanzapine. In other embodiments, the subject does not comprise the SULT4A1-1 haplotype, and the pharmacotherapeutic is a non-olanzapine antipsychotic treatment. Steps for determining the SUTL4A1-1 haplotype may be carried out in vitro. In certain aspects, the treatment plan selected is a treatment plan for schizophrenia.

Certain aspects of the invention may involve a method for treating a subject having a psychotic disorder and determined to have a SULT4A1-1 haplotype, comprising treating the subject with olanzapine. In some further aspects, the invention may include a method for treating a subject having a psychotic disorder and determined not to have a SULT4A1-1 haplotype, comprising treating the subject with a non-olanzapine antipsychotic treatment, such as treating with risperidone, ziprasidone, or perphenazine. In certain embodiments, the psychotic disorder is schizophrenia.

In other embodiments, there is provided a method for determining response to treatment with risperidone for a human subject having or suspected of having schizophrenia comprising determining the SULT4A1-1 haplotype in a sample, wherein a) if the human subject comprises the SULT4A1-1 haplotype, the subject is less likely to exhibit a favorable response to risperidone; and b) if the subject does not comprise the SUTL4A1-1 haplotype, the subject is more likely to exhibit a favorable response to risperidone.

In other embodiments, there is provided a method for determining elevated risk of a patient to discontinue treatment with risperidone due to a treatment-emergent adverse event or lack of efficacy comprising determining the SULT4A1-1 haplotype in a sample, wherein a) if the human subject comprises the SULT4A1-1 haplotype, the subject is more likely to exhibit a propensity to discontinue treatment due to a treatment-emergent adverse event or lack of efficacy; and b) if the subject does not comprise the SUTL4A1-1 haplotype, the subject is more likely to exhibit a propensity to continue treatment. Steps for determining the SUTL4A1-1 haplotype and determining the propensity of the subject to continue or discontinue treatment may be carried out in vitro.

In certain embodiments, there is also provided a method for selecting a pharmacotherapeutic treatment plan for a human subject having the potential for suffering a treatment-emergent adverse event or lack of efficacy when treated with risperidone, comprising determining the SULT4A1-1 haplotype in a sample, wherein a) if the human subject comprises the SULT4A1-1 haplotype, the subject is more likely to experience a treatment-emergent adverse event or lack of efficacy when treated with risperidone; and b) if the subject does not comprise the SUTL4A1-1 haplotype, the subject is not more likely to experience a treatment-emergent adverse event or lack of efficacy when treated with risperidone; selecting a pharmacotherapeutic treatment plan based on the SULT4A1-1 haplotype; and treating the subject with the selected pharmacotherapeutic treatment. In some embodiments, the pharmacotherapeutic is risperidone, and the subject does not comprise the

SULT4A1-1 haplotype. In other aspects, the pharmacotherapeutic is an antipsychotic other than risperidone, and the subject comprises the SULT4A1-1 haplotype. For example, the antipsychotic other than risperidone may be olanzapine, quetiapine, ziprasidone, or perphenazine. Steps for determining the SUTL4A1-1 haplotype may be carried out in vitro. In certain aspects, the treatment plan selected is a treatment plan for schizophrenia.

Certain aspects of the invention may involve a method for treating a subject having a psychotic disorder and determined to not have the SULT4A1-1 haplotype, comprising treating the subject with risperidone. In some further aspects, the invention may include a method for treating a subject having a psychotic disorder and determined to have a SULT4A1-1 haplotype, comprising treating the subject with a non-risperidone antipsychotic treatment such as treating with olanzapine, quetiapine, ziprasidone, or perphenazine. In certain embodiments, the psychotic disorder is schizophrenia.

In other embodiments, there is provided a method for determining response to treatment with quetiapine for a human subject having or suspected of having schizophrenia comprising determining the SULT4A1-1 haplotype in a sample, wherein if the human subject comprises the SULT4A1-1 haplotype the subject is more likely to exhibit a favorable response to quetiapine and if the subject does not comprise the SULT4A1-1 haplotype the subject is less likely to exhibit a favorable response to quetiapine.

In certain embodiments, there is also provided a method for treating a human subject having or suspected of having a psychotic disorder comprising a) selecting a subject that has been determined to have a SULT4A1-1 haplotype, defined as a haplotype comprising a C allele at rs763120, a combination of an A allele at rs2285162 and a G allele at rs2285167, or the combination of a T allele atrs2285166 and G allele at rs2285167, and treating the subject with quetiapine or olanzapine; or b) selecting a subject that has been determined not to have the SULT4A1-1 haplotype and treating the subject with an antipsychotic treatment other than quetiapine or olanzapine.

Certain aspects of the invention may involve a method for treating a subject having a psychotic disorder and determined to have a SULT4A1-1 haplotype, comprising treating the subject with quetiapine or olanzapine. In some further aspects, the invention may include a method for treating a subject having a psychotic disorder and determined not to have a SULT4A1-1 haplotype, comprising treating the subject with a an antipsychotic treatment other than quetiapine or olanzapine, such as treating with risperidone, ziprasidone, or perphenazine. In certain embodiments, the psychotic disorder is schizophrenia.

Certain aspects of the invention may involve a method for treating a subject comprising selecting a subject that is determined to have a SULT4A1-1 haplotype and developing an appropriate treatment plan. Other aspects of the invention may involve a method for treating a subject comprising selecting a subject that is determined not to have a SULT4A1-1 haplotype and developing an appropriate treatment plan. Prior determination of a patient's SULT4A1-1 haplotype status may be obtained from or reported by a sequencing or a genotyping service, a laboratory, a scientist, or any genetic test platforms.

Some aspects involve an antipsychotic pharmacotherapeutic for use in treating a subject having a psychotic disorder. In some embodiments, the selection of the antipsychotic is based on the presence of absence of a SULT4A1-1 haplotype in the subject to be treated. For example, provided is an antipsychotic pharmacotherapeutic selected from olanzapine and quetiapine for use in treating a subject having a psychotic disorder, wherein the subject has been determined to comprise a SULT4A1-1 haplotype defined as comprising a rs763120(C) allele, a combination of a rs2285162(A) allele and a rs2285167(G) allele, or a combination of a rs2285166(T) allele and a rs2285167(G) allele. In certain aspects, the pharmacotherapeutic is olanzapine or quetiapine. In some embodiments, the psychotic disorder is schizophrenia.

Also provided is an antipsychotic pharmacotherapeutic other than olanzapine or quetiapine for use in treating a subject having a psychotic disorder, wherein the subject has been determined not to comprise a SULT4A1-1 haplotype defined as comprising a rs763120(C) allele, a combination of a rs2285162(A) allele and a rs2285167(G) allele, or a combination of a rs2285166(T) allele and a rs2285167(G) allele. The antipsychotic other than olanzapine or quetiapine may be any non-olanzapine or non-quetiapine antipsychotic pharmacotherapeutic. In certain aspects, the pharmacotherapeutic is risperidone, perphenazine, or ziprasidone. In some embodiments, the psychotic disorder is schizophrenia.

The SULT4A1-1 haplotype characterization may also apply to diagnosis and prognosis of psychotic disorders. For example, there may be provided a method of assessing the severity of such a disorder, comprising obtaining genetic information about the subject by the methods disclosed above, wherein if the subject comprises a SULT4A1-1 haplotype, the subject is at a higher risk for having a more severe disorder, and wherein if the subject does not comprise the SULT4A1-1 haplotype, the subject is at a lower risk for having a more severe disorder. The assessment may be stored in a tangible medium, such as a computer-readable disk, a solid state memory device, and an optical storage device.

Certain aspects of the present invention also contemplate the preparation of kits or arrays for use in accordance with the present invention. Suitable kits include various reagents for use in accordance with the present invention in suitable containers and packaging materials, including tubes, vials, and shrink-wrapped and blow-molded packages. Such an array or a kit may comprise a plurality of primers or probes specific for a SULT4A1-1 haplotype. The array may be a genotyping chip. Also a tangible, computer-readable medium comprising a SNP profile of a subject may also be provided, wherein the SNP profile exhibits the presence or absence of a SULT4A1-1 haplotype.

Embodiments discussed in the context of methods and/or compositions of the invention may be employed with respect to any other method or composition described herein. Thus, an embodiment pertaining to one method or composition may be applied to other methods and compositions of the invention as well.

As used herein the specification, “a” or “an” may mean one or more. As used herein in the claim(s), when used in conjunction with the word “comprising”, the words “a” or “an” may mean one or more than one.

The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” As used herein “another” may mean at least a second or more.

Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

FIG. 1: Linkage disequilibrium for the Caucasian sample. The Haploview output shows pairwise correlation coefficients (r2 values in % are given in the diamonds) for the 11 SULT4A1 SNPs from the CATIE study (N=836 persons). Based on the total sample of cases and controls, Haploview identifies a single haplotype block for the 11 SNPs (Barrett et al., 2005). The locations of previously studied SNPs, rs138097 (the SNP is in position 31 of SEQ ID NO:8) and rs138110 (the SNP is in position 31 of SEQ ID NO:13), are indicated by arrows. Only the latter was included in the CATIE study. Previously studied marker rs138060 (the SNP is in position 31 of SEQ ID NO:1) is located approximately 5 kb to the left of rs138067 (the SNP is in position 31 of SEQ ID NO:2), outside the region covered by the SULT4A1 SNPs in CATIE.

FIG. 2: Linkage disequilibrium for the African American sample. The Haploview output shows pairwise correlation coefficients (r2 values in %) for the 11 CATIE SNPs (N=442 persons).

FIG. 3: Response of SULT4A1-1 positive subjects in CATIE at various response thresholds.

FIG. 4: Response of SULT4A1-1 negative subjects in CATIE at various respones thresholds.

FIG. 5: Percentage of SULT4A1-1 positive patients remaining in phase 1 of the CATIE trial at various time points.

FIG. 6: Percentage of SULT4A1-1 negative patients remaining in phase 1 of the CATIE trial at various time points.

FIG. 7: An exemplary embodiment of risk management involving SULT4A1-1 determination.

FIG. 8: Kaplan-Meier survival curves for the SULT4A1-1 negative and SULT4A1-1 positive patient populations. Each plot corresponds to an individual atypical antipsychotic in the CATIE trial. The curves model the fraction of the trial population that will not have a hospitalization event as a function of time. Survival fractions are adjusted for the number of subjects remaining in the trial at each time point. Vertical slashes correspond to patients discontinuing the drug, either due to drug switching or stopping participation in the trial.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Choosing the correct antipsychotic medication for patients suffering from severe neuropsychiatric illnesses is a major challenge. Fewer than one in three patients suffering from schizophrenia and related disorders will have a robust improvement in symptoms on the first antipsychotic drug prescribed. One out of three patients will be resistant to commonly used drugs. Furthermore, the metabolic side-effects of antipsychotic drugs, most commonly seen with olanzapine and clozapine, result in low compliance, with 50% of patients discontinuing drug use within 6 months of prescription, leading to relapse (return of psychosis) and hospitalization.

Therefore, methods and compositions of the present invention will help to meet this challenge by assisting physicians, patients, lab, or pharmacists with selection or recommendation of appropriate antipsychotic medication. Specifically, the present inventors have used a specific haplotype of the SULT4A1 gene for pharmacogenomic applications in related psychotic disorders, i.e., assessing the impact of genetic variation on drug response and side-effect profiles.

Examples of variation in drug response include any of the following: efficacy, side-effect profile, treatment maintenance and discontinuation rates, return to work status, hospitalizations, suicidality, total healthcare cost, social functioning scales, response to non-pharmacological treatments, and dose response curves. Efficacy includes but is not limited to the following definition: >=20 decrease in Total PANSS score. Side-effect profile includes one or more of weight gain, metabolic dysfunction, lipid dysfunction, movement disorders, and extrapyramidal symptoms.

Further embodiments and advantages of the invention are described below.

I. DEFINITIONS

As defined herein, “Schizophrenia” or “SZ” includes the SZ-spectrum disorders, Schizotypal Personality Disorder (SPD) and Schizoaffective Disorder (SD), as well as Schizophrenia under the narrower, DSM-IV definition.

As used herein, a “haplotype” is one or a set of markers (e.g., polymorphisms) that are grouped closely together on a given chromosome and are usually inherited as a group. As used herein, the term “polymorphism” refers to the condition in which there is a variation in the DNA sequence between some members of a species. A haplotype can include, but not be limited to, a variety of genetic markers, including indels (insertions or deletions of the DNA at particular locations on the chromosome); single nucleotide polymorphisms (SNPs) in which a particular nucleotide is changed; microsatellites; and minisatellites.

As used herein, a “SULT4A1-1 haplotype,” i.e., a “SULT4A1-1 positive haplotype,” refers to a haplotype comprising rs763120(C) (a C allele in position 31 of SEQ ID NO:15), a combination of rs2285162(an A allele at position 31 of SEQ ID NO:6)-rs2285167(a G allele at position 31 of SEQ ID NO:9), a combination of rs2285166(a T allele at position 31 of SEQ ID NO:14)-rs2285167(G), or a haplotype that is in complete linkage disequilibrium with the combination rs2285162(A)-rs2285167(G) or rs2285166(T)-rs2285167(G), such as a haplotype comprising rs763120 (a C allele at position 31 of SEQ ID NO:15). The sequence identifiers are intended for SNP sequence identification only and an ordinary person of skill in the art would recognize some subjects may have sequence heterogeneity or polymorphism at other positions of those sequences.

“Linkage disequilibrium” occurs when the observed frequencies of associations of alleles for different polymorphisms in a population do not agree with frequencies predicted by multiplying together the allele frequencies for the individual genetic markers, thus resulting in a specific haplotype in the population.

The term “chromosome” as used herein refers to a gene carrier of a cell that is derived from chromatin and comprises DNA and protein components (e.g., histones). The conventional internationally recognized individual human genome chromosome numbering identification system is employed herein. The size of an individual chromosome can vary from one type to another with a given multi-chromosomal genome and from one genome to another. In the case of the human genome, the entire DNA mass of a given chromosome is usually greater than about 100,000,000 base pairs. For example, the size of the entire human genome is about 3×109 base pairs.

The term “gene” refers to a DNA sequence in a chromosome that codes for a product (either RNA or its translation product, a polypeptide). A gene contains a coding region and includes regions preceding and following the coding region (termed respectively “leader” and “trailer”). The coding region is comprised of a plurality of coding segments (“exons”) and intervening sequences (“introns”) between individual coding segments.

The term “probe” refers to an oligonucleotide. A probe can be single stranded at the time of hybridization to a target. As used herein, probes include primers, i.e., oligonucleotides that can be used to prime a reaction, e.g., a PCR reaction.

The term “label” or “label containing moiety” refers in a moiety capable of detection, such as a radioactive isotope or group containing same, and nonisotopic labels, such as enzymes, biotin, avidin, streptavidin, digoxygenin, luminescent agents, dyes, haptens, and the like. Luminescent agents, depending upon the source of exciting energy, can be classified as radioluminescent, chemiluminescent, bioluminescent, and photoluminescent (including fluorescent and phosphorescent). A probe described herein can be bound, e.g., chemically bound to label-containing moieties or can be suitable to be so bound. The probe can be directly or indirectly labeled.

The term “direct label probe” (or “directly labeled probe”) refers to a nucleic acid probe whose label after hybrid formation with a target is detectable without further reactive processing of hybrid. The term “indirect label probe” (or “indirectly labeled probe”) refers to a nucleic acid probe whose label after hybrid formation with a target is further reacted in subsequent processing with one or more reagents to associate therewith one or more moieties that finally result in a detectable entity.

The terms “target,” “DNA target,” or “DNA target region” refers to a nucleotide sequence that occurs at a specific chromosomal location. Each such sequence or portion is preferably at least partially, single stranded (e.g., denatured) at the time of hybridization. When the target nucleotide sequences are located only in a single region or fraction of a given chromosome, the term “target region” is sometimes used. Targets for hybridization can be derived from specimens which include, but are not limited to, chromosomes or regions of chromosomes in normal, diseased or malignant human cells, either interphase or at any state of meiosis or mitosis, and either extracted or derived from living or postmortem tissues, organs or fluids; germinal cells including sperm and egg cells, or cells from zygotes, fetuses, or embryos, or chorionic or amniotic cells, or cells from any other germinating body; cells grown in vitro, from either long-term or short-term culture, and either normal, immortalized or transformed; inter- or intraspecific hybrids of different types of cells or differentiation states of these cells; individual chromosomes or portions of chromosomes, or translocated, deleted or other damaged chromosomes, isolated by any of a number of means known to those with skill in the art, including libraries of such chromosomes cloned and propagated in prokaryotic or other cloning vectors, or amplified in vitro by means well known to those with skill; or any forensic material, including but not limited to blood, or other samples.

The term “hybrid” refers to the product of a hybridization procedure between a probe and a target. The term “hybridizing conditions” has general reference to the combinations of conditions that are employable in a given hybridization procedure to produce hybrids, such conditions typically involving controlled temperature, liquid phase, and contact between a probe (or probe composition) and a target. Conveniently and preferably, at least one denaturation step precedes a step wherein a probe or probe composition is contacted with a target. Guidance for performing hybridization reactions can be found in Ausubel et al. (2003). Aqueous and nonaqueous methods are described in that reference and either can be used. Hybridization conditions may be a 50% formamide, 2×SSC wash for 10 minutes at 45° C. followed by a 2×SSC wash for 10 minutes at 37° C.

Calculations of “identity” between two sequences can be performed as follows. The sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequence for optimal alignment and non-identical sequences can be disregarded for comparison purposes). The length of a sequence aligned for comparison purposes is at least 30%, e.g., at least 40%, 50%, 60%, 70%, 80%, 90% or 100%, of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

As used herein, the term “substantially identical” is used to refer to a first nucleotide sequence that contains a sufficient number of identical nucleotides to a second nucleotide sequence such that the first and second nucleotide sequences have similar activities. Nucleotide sequences that are substantially identical are at least 80%, e.g., 85%, 90%, 95%, 97% or more, identical.

The term “nonspecific binding DNA” refers to DNA which is complementary to DNA segments of a probe, which DNA occurs in at least one other position in a genome, outside of a selected chromosomal target region within that genome. An example of nonspecific binding DNA comprises a class of DNA repeated segments whose members commonly occur in more than one chromosome or chromosome region. Such common repetitive segments tend to hybridize to a greater extent than other DNA segments that are present in probe composition.

As used herein, the term “stratification” refers to the creation of a distinction between subjects on the basis of a characteristic or characteristics of the subjects. Generally, in the context of clinical trials, the distinction is used to distinguish responses or effects in different sets of patients distinguished according to the stratification parameters. In some embodiments, stratification includes distinction of subject groups based on the presence or absence of a SULT4A1-1 haplotype described herein. The stratification can be performed, e.g., in the course of analysis, or can be used in creation of distinct groups or in other ways.

As used herein, “Typical” antipsychotics refer to so called first generation or classical antipsychotics. This class of drugs was first developed in the 1950s. Some examples include: Chlorpromazine (Largactil, Thorazine), Fluphenazine (Prolixin), Haloperidol (Haldol, Serenace), Molindone, Thiothixene (Navane), Thioridazine (Mellaril), Trifluoperazine (Stelazine), Loxapine (Loxapac, Loxitane), Perphenazine, Prochlorperazine (Compazine, Buccastem, Stemetil), Pimozide (Orap), Zuclopenthixol (Clopixol). This class of drug can cause serious adverse events, particularly Tardive Dyskinesia, a movement disorder.

As used herein, “Atypical” antipsychotics refer to a newer class of antipsychotic drugs first introduced in the 1990s. This class of drugs includes the following examples:

Clozapine (Clozaril) (FDA-approval: 1990): Available in oral tablets and dissolving tablets (FazaClo).

Risperidone (Risperdal) (FDA-approval: 1993): Available in oral tablets, dissolving tablets, liquid form, and extended release intramusclar injection.

Olanzapine (Zyprexa) (FDA-approval: 1996): Available in oral tablets, dissolving tablets, and intramuscular injection.

Quetiapine (Seroquel) (FDA-approval: 1997): Available only in oral tablets.

Ziprasidone (Geodon) (FDA-approval: 2001): Available in oral capsules and intramuscular injection.

Aripiprazole (Abilify) (FDA-approval: 2002): Available in oral tablets and dissolving tablets.

Paliperidone (Invega) (FDA-approval: 2006): Available in extended-release oral tablets.

Asenapine (Saphris) (FDA-approval: 2009): Available in sublingual tablets.

Lurasidone (Latuda) (FDA-approval: 2010): Available in oral tablets.



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stats Patent Info
Application #
US 20120277211 A1
Publish Date
11/01/2012
Document #
13508191
File Date
11/04/2010
USPTO Class
51421113
Other USPTO Classes
514220, 51425941, 5142258, 51425404, 435/611, 506/9
International Class
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Drawings
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