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WO2006126199A2 - Methodes et compositions pour traiter la schizophrenie - Google Patents

Methodes et compositions pour traiter la schizophrenie Download PDF

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Publication number
WO2006126199A2
WO2006126199A2 PCT/IL2006/000614 IL2006000614W WO2006126199A2 WO 2006126199 A2 WO2006126199 A2 WO 2006126199A2 IL 2006000614 W IL2006000614 W IL 2006000614W WO 2006126199 A2 WO2006126199 A2 WO 2006126199A2
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subject
another embodiment
arts
protein
schizophrenia
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PCT/IL2006/000614
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English (en)
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WO2006126199A3 (fr
Inventor
Sarit Larisch
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Fund For Medical Research Development Of Infrastructure & Health Services Rambam Medical Center
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Publication of WO2006126199A2 publication Critical patent/WO2006126199A2/fr
Publication of WO2006126199A3 publication Critical patent/WO2006126199A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4747—Apoptosis related proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention provides methods for treating or reducing an incidence of a disease, disorder, or symptom, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron, comprising contacting a subject with a compound or composition that alters an activity or expression of an ARTS (Apoptosis Related Protein in the TGF- ⁇ Signaling Pathway) protein.
  • This invention also provides methods for determining a predisposition or susceptibility of a subject to the disease, disorder, or symptom and methods for identifying a compound or composition useful for prophylactic or therapeutic treatment of a schizophrenia, comprising detecting ARTS protein activity or expression or determining a sequence of a gene encoding an ARTS protein.
  • One of the most debilitating psychiatric disorders is schizophrenia, which affects about 1 % of the population.
  • the symptoms of this disease include delusions, hallucinations, unusual thoughts, poor motivation, apathy and social withdrawal with affective flattening.
  • Efforts to identify the underlying genetic and molecular mechanisms in schizophrenia are currently focused on three general lines of inquiry: (i) examination of the mechanism of action of drugs that alleviate the symptoms of schizophrenia, (ii) examination of neuroanatomical abnormalities in the brains of schizophrenia patients, and (iii) examination of candidate genes that confer susceptibility to schizophrenia.
  • Schizophrenic brains exhibit various neuro-pathological changes in size, volume and structure as compared to normal brains. An improved understanding of the causes of schizophrenia is needed to treat this disorder.
  • This invention provides methods for treating or reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron, comprising contacting the subject with a compound or composition that alters an activity or expression of an ARTS protein.
  • This invention also provides methods for determining predisposition or susceptibility of a subject to the disease, disorder, or symptom, and methods for identifying a compound or composition useful for prophylactic or therapeutic treatment of schizophrenia, comprising detecting ARTS protein activity or expression or determining a sequence of a gene encoding an ARTS protein.
  • the present invention provides a method for reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that reduces an activity of an ARTS protein, thereby reducing an incidence of a disease, disorder, or symptom in a subject.
  • the present invention provides a method for reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that reduces an expression of an ARTS protein, thereby reducing an incidence of a disease, disorder, or symptom in a subject.
  • the present invention provides a method for treating a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that reduces an activity of an ARTS protein, thereby treating a disease, disorder, or symptom in a subject.
  • the present invention provides a method for treating a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that reduces an expression of an ARTS protein, thereby treating a disease, disorder, or symptom in a subject.
  • the present invention provides a method for reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with an ARTS protein mimetic compound, thereby reducing an incidence of a disease, disorder, or symptom in a subject.
  • the present invention provides a method for treating a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with an ARTS protein mimetic compound, thereby treating a disease, disorder, or symptom in a subject.
  • the present invention provides a method for reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that increases an activity of an ARTS protein, thereby reducing an incidence of a disease, disorder, or symptom in a subject.
  • the present invention provides a method for reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that increases an expression of an ARTS protein, thereby reducing an incidence of a disease, disorder, or symptom in a subject.
  • the present invention provides a method for treating a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that increases an activity of an ARTS protein, thereby treating a disease, disorder, or symptom in a subject.
  • the present invention provides a method for treating a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that increases an expression of an ARTS protein, thereby treating a disease, disorder, or symptom in a subject.
  • the present invention provides a method for determining a predisposition or susceptibility of a subject to a disease, disorder, or symptom, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising detecting an activity of an ARTS protein in the neuron and comparing the activity to a reference standard thereof, whereby a difference between the activity and the reference standard indicates that the subject has a predisposition or susceptibility to the disease, disorder, or symptom.
  • the present invention provides a method for determining a predisposition or susceptibility of a subject to a disease, disorder, or symptom, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising detecting an expression of an ARTS protein in the neuron and comparing the expression to a reference standard thereof, whereby a difference between the expression and the reference standard indicates that the subject has a predisposition or susceptibility to the disease, disorder, or symptom.
  • the present invention provides a method for determining a predisposition or susceptibility of a subject to a disease, disorder, or symptom, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising determining a sequence of a gene encoding an ARTS protein or a promoter or enhancer sequence thereof in the subject and comparing the sequence to a reference standard thereof.
  • the present invention provides a method for identifying a compound or composition useful for prophylactic or therapeutic treatment of a schizophrenia, comprising (a) contacting a first neuron with the compound or composition; (b) measuring a first activity of an ARTS protein in the first neuron; (c) contacting a second neuron with the compound or composition; (d) measuring a second activity of an ARTS protein in the second neuron; and (e) comparing the first activity with the second activity.
  • the first activity is altered relative to the second activity, then the compound or composition is useful for prophylactic or therapeutic treatment of the schizophrenia.
  • the present invention provides a method for identifying a compound or composition useful for prophylactic or therapeutic treatment of a schizophrenia, comprising (a) contacting a first neuron with the compound or composition; (b) measuring a first expression of an ARTS protein in the first neuron; (c) contacting a second neuron with the compound or composition; (d) measuring a second expression of an ARTS protein in the second neuron; and (e) comparing the first expression with the second expression.
  • the first expression is altered relative to the second expression, then the compound or composition is useful for prophylactic or therapeutic treatment of the schizophrenia.
  • Figure 1 Part 1 : ARTS protein staining is significantly reduced in schizophrenic patients.
  • D ARTS protein staining is significantly reduced in schizophrenic patients.
  • E-F Percentage of neuronal cell body non-reactive, weak-staining, and strong-staining schizophrenia brains (E) and major depression brains (F).
  • E Percentage of neuronal cell body non-reactive, weak-staining, and strong-staining schizophrenia brains (E) and major depression brains (F).
  • E Percentage of neuronal cell body non-reactive, weak-staining, and strong-staining schizophrenia brains (E) and major depression brains (F).
  • Part 2 Grayscale version of Figure IB; blue appears as gray, and red appears as black.
  • Figure 2 ARTS protein expression is reduced in schizophrenic patients.
  • Western blot analysis of frontal cortex brain samples from schizophrenic patients and normal controls A.
  • the average ratio of the staining intensity levels of ARTS:actin was significantly lower in the schizophrenic samples than in normal controls (B).
  • Figure 4 Low apoptotic index by TUNEL assay in brains of schizophrenic patients.
  • A. A positive TUNEL sample in frontal cortex section.
  • B. The number of brains positive for apoptosis in the schizophrenic group was lower than in each of the other diagnostic groups.
  • FIG. 5 ARTS protein is expressed in post-mitotic neuronal cells, and higher ARTS levels induce apoptosis in these cells.
  • A-B CAD cells before (A) and after (B) differentiation to postmitotic neuronal-like cells.
  • C Both CAD and dCAD cells express high levels of ARTS.
  • D Over- expression of ARTS results in elevated apoptosis levels, as shown by a 3-fold increase in caspase-3 activity after 8 hr.
  • Figure 6 9-mer peptides derived from the ARTS C-terminus exhibit pro-apoptotic activity. Cells were incubated with no peptide ("no peptide") or with peptides corresponding to residues 1-9 (“pepl”), 10-18 (“pep2”), or 19-27 (“pep3”) of the ARTS C-terminus.
  • This invention provides methods for treating or reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron, comprising contacting the subject with a compound or composition that alters an activity or expression of an ARTS (Apoptosis Related Protein in the TGF- ⁇ Signaling Pathway) protein.
  • ARTS Apoptosis Related Protein in the TGF- ⁇ Signaling Pathway
  • This invention also provides methods for determining predisposition or susceptibility of a subj ect to the disease, disorder, or symptom, and methods for identifying a compound or composition useful for prophylactic or therapeutic treatment of schizophrenia, comprising detecting ARTS protein activity or expression or determining a sequence of a gene encoding an ARTS protein.
  • the present invention provides a method for reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that reduces an activity of an ARTS protein, thereby reducing an incidence of a disease, disorder, or symptom in a subject.
  • the ARTS protein of methods of the present invention has the amino acid (AA) sequence set forth in SEQ ID No: 1.
  • the ARTS protein is homologous to the sequence set forth in SEQ ID No : 1.
  • the ARTS protein is a variant of the sequence set forth in SEQ ID No: 1.
  • the ARTS protein is an isoform of the sequence set forth in SEQ ID No: 1 :
  • the present invention provides a method for reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subj ect, comprising contacting the subj ect with a compound or composition that reduces an expression of an ARTS protein, thereby reducing an incidence of a disease, disorder, or symptom in a subject.
  • antagonizing ARTS activity or expression prevents the onset of schizophrenia.
  • antagonizing ARTS activity or expression prevents the activation of schizophrenia.
  • the activation is activation in response to a trigger or an environmental stressor.
  • the present invention provides a method for treating a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that reduces an activity of an ARTS protein, thereby treating a disease, disorder, or symptom in a subject.
  • the present invention provides a method for treating a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that reduces an expression of an ARTS protein, thereby treating a disease, disorder, or symptom in a subject.
  • the present invention provides a method for reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with an ARTS protein mimetic compound, thereby reducing an incidence of a disease, disorder, or symptom in a subject.
  • the present invention provides a method for treating a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with an ARTS protein mimetic compound, thereby treating a disease, disorder, or symptom in a subject.
  • the present invention provides a method for reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that increases an activity of an ARTS protein, thereby reducing an incidence of a disease, disorder, or symptom in a subject.
  • the present invention provides a method for reducing an incidence of a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that increases an expression of an ARTS protein, thereby reducing an incidence of a disease, disorder, or symptom in a subject.
  • the present invention provides a method for treating a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising contacting the subject with a compound or composition that increases an activity of an ARTS protein, thereby treating a disease, disorder, or symptom in a subject.
  • the present invention provides a method for treating a disease, disorder, or symptom in a subject, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subj ect, comprising contacting the subj ect with a compound or composition that increases an expression of an ARTS protein, thereby treating a disease, disorder, or symptom in a subject.
  • the increased ARTS expression provided by a method of the present invention is, in another embodiment, an over-expression.
  • the increased expression is an exogenous expression.
  • the increased expression compensates for decreased endogenous ARTS expression.
  • the increased expression compensates for absent endogenous ARTS expression.
  • the increased expression compensates for non-detectable endogenous ARTS expression.
  • the ARTS activity provided in a method of the present invention is an activity of a neuro-protective ARTS isoform distinct from the isoform represented by SEQ ID No: 1.
  • the ARTS activity provided is an activity of an ARTS isoform represented by SEQ ID No: 1.
  • the ARTS isoform is homologous to SEQ ID No: 1.
  • the present invention provides a method for determining a predisposition or susceptibility of a subject to a disease, disorder, or symptom, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising detecting an activity of an ARTS protein in the neuron and comparing the activity to a reference standard thereof, whereby a difference between the activity and the reference standard indicates that the subject has a predisposition or susceptibility to the disease, disorder, or symptom.
  • the present invention provides a method for determining a predisposition or susceptibility of a subject to a disease, disorder, or symptom, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising detecting an expression of an ARTS protein in the neuron and comparing the expression to a reference standard thereof, whereby a difference between the expression and the reference standard indicates that the subject has a predisposition or susceptibility to the disease, disorder, or symptom.
  • the alteration in ARTS activity or expression is due to a genetic difference between the subject and the general population.
  • the alteration in ARTS activity or expression is due to an environmental stressor.
  • the alteration in ARTS activity or expression is due to a combination of the above factors.
  • the alteration in ARTS activity or expression is due to altered expression of a gene encoding an ARTS protein.
  • the alteration in ARTS activity or expression is due to altered intracellular degradation of ARTS protein.
  • the present invention provides a method for determining a predisposition or susceptibility of a subject to a disease, disorder, or symptom, wherein the disease, disorder, or symptom comprises a dysregulated apoptosis in a neuron of the subject, comprising determining a sequence of a gene encoding an ARTS protein or a promoter or enhancer sequence thereof in the subject and comparing the sequence to a reference standard thereof.
  • a particular mutation indicates that the subj ect has a predisposition or susceptibility to the disease, disorder, or symptom.
  • a mutation in a particular region of the gene indicates that the subject has a predisposition or susceptibility to the disease, disorder, or symptom.
  • a difference between the sequence and the reference standard indicates that the subject has a predisposition or susceptibility to the disease, disorder, or symptom.
  • the mutation is a somatic mutation.
  • the mutation is in the coding region of ARTS.
  • the mutation is in a location that affects expression of the ARTS gene, hi another embodiment, the mutation is in a location that affects methylation of the ARTS gene, hi another embodiment, the mutation is a germ-line mutation.
  • the mutation causes a reduction in ARTS levels in the subject.
  • the mutation causes a reduction in ARTS activity in the subject.
  • Each possibility represents a separate embodiment of the present invention.
  • a method of present invention comprises the steps of determining the sequence of an ARTS gene in a sample from the subject.
  • the sample is a blood sample.
  • the sample is a cerebrospinal sample, hi another embodiment, the sample is a neuron sample.
  • the sample is another other type of sample known in the art. Each possibility represents a separate embodiment of the present invention.
  • a range to be used as a reference standard is defined using a statistical method.
  • the statistical method is a CART analysis method.
  • the statistical method is any other statistical method known in the art.
  • the range is defined by an empirical determination of the best range to use for classifying the subjects; for example, by comparing the diagnostic power of methods utilizing different ranges.
  • a reference standard used in a method of the present invention is determined based on values or sequences from the general population.
  • the reference standard is determined based on a subgroup of the general population, hi another embodiment, the reference standard is a gender-matched reference standard, hi another embodiment, the reference standard is not gender matched.
  • Each method represents a separate embodiment of the present invention.
  • ARTS protein sensitizes neuronal cells to apoptosis (Example 5).
  • an aberrant level of ARTS protein activity and/or expression confers a predisposition or susceptibility to a disease, disorder, or symptom that comprises a dysregulated apoptosis in a neuron.
  • an aberrant level of ARTS protein activity and/or expression is caused by a germ-line mutation.
  • an aberrant level of ARTS protein activity and/or expression is caused by a somatic mutation.
  • an aberrant level of ARTS protein activity and/or expression is caused by aberrant transcriptional, post- transcriptional, translational, or post-translational processing of ARTS protein
  • an aberrant level of ARTS protein activity and/or expression is caused by aberrant processing of a protein that interacts with or regulates ARTS protein.
  • apro-apoptotic ARTS isoform e.g. the ARTS protein with the sequence set forth in SEQ ID No: 1 sensitizes cells to apoptosis.
  • an anti-apoptotic ARTS isoform is expressed in the brain, hi another embodiment, a decreased level or activity of the anti-apoptotic ARTS isoform renders cells susceptible to apoptosis.
  • the apoptosis occurs immediately after the alteration is ARTS activity or expression.
  • the apoptosis is triggered by a subsequent event.
  • the subsequent event is a life event (e.g. a stressful event).
  • the subsequent event is an additional mutation or change is a pattern of processing of ARTS protein or another protein.
  • Predisposition in another embodiment, refers to an increased likelihood of developing the disease, disorder, or symptom. In another embodiment, “predisposition” refers to an increased likelihood of currently having the disease, disorder, or symptom, hi another embodiment, the increased likelihood is about 10% greater than the general population. In another embodiment, the increased likelihood is about 20% greater than the general population. In another embodiment, the increased likelihood is about 30% greater than the general population, hi another embodiment, the increased likelihood is about 40% greater than the general population, hi another embodiment, the increased likelihood is about 50% greater than the general population. In another embodiment, the increased likelihood is about 60% greater than the general population, hi another embodiment, the increased likelihood is about 80% greater than the general population. In another embodiment, the increased likelihood is about 2-fold greater than the general population.
  • the increased likelihood is several-fold greater than the general population, hi another embodiment, the increased likelihood is assessed relative to a subject testing negative for the aberrant level of ARTS protein activity and/or expression. In another embodiment, the increased likelihood is assessed relative to a subject in a particular subgroup of the general population; e.g. males, females, or age- matched subjects. Each possibility represents a separate embodiment of the present invention.
  • the disease, disorder, or symptom treated or detected by a method of the present invention is a schizophrenia, hi another embodiment, the schizophrenia is catatonic schizophrenia, hi another embodiment, the schizophrenia is paranoid schizophrenia.
  • the schizophrenia is disorganized schizophrenia, hi another embodiment, the schizophrenia is undifferentiated schizophrenia, hi another embodiment, the schizophrenia is residual schizophrenia.
  • the schizophrenia is negative or deficit schizophrenia.
  • the disease, disorder, or symptom is any other type of schizophrenia known in the art
  • the schizophrenia is caused by a dysregulated expression of ARTS protein in a neuron.
  • the schizophrenia is caused by a dysregulated activity of
  • the schizophrenia is caused by an increased apoptosis in a neuron. In another embodiment, the schizophrenia is caused by a decreased apoptosis in a neuron.
  • the disease, disorder, or symptom treated or detected by a method of the present invention is a psychosis.
  • a method of the present invention is used to treat or reduce the incidence of a symptom of a disease or disorder that comprises a dysregulated apoptosis in a neuron.
  • the symptom is a psychosis.
  • the symptom is an inability to experience pleasure.
  • the symptom is a lack of emotion.
  • the symptom is a loss of motivation to succeed or accomplish goals.
  • the symptom is difficulty focusing or paying attention, difficulty processing information, confusion, and/or having fragmented thoughts.
  • the symptom is hallucinations.
  • the symptom is delusions.
  • the symptom is jerking eye movements.
  • the symptom is self neglect.
  • the symptom is any other type of playful or disorganized behavior. Known in the art: hi another embodiment, the symptom is any other symptom of a schizophrenia known in the art.
  • the disease, disorder, or symptom that is treated, prevented or detected by a method of the present invention is associated with an abnormally high degree or amount of apoptosis.
  • the disease, disorder, or symptom is associated with an abnormally low degree or amount of apoptosis.
  • the disease, disorder, or symptom is associated with a temporally abnormal pattern of apoptosis.
  • the disease, disorder, or symptom is associated with a spatially abnormal pattern of apoptosis.
  • each disease, disorder, or symptom represents a separate embodiment of the present invention.
  • the brains of schizophrenic subjects exhibit lower levels of ARTS than brains of non-schizophrenic subjects (Examples 1-2).
  • providing ARTS activity to brains of schizophrenic subjects alleviates the disease.
  • providing ARTS activity to brains of subjects prevents the onset of schizophrenia.
  • antagonizing ARTS activity in the brains of subjects prevents or treats schizophrenia.
  • antagonizing ARTS activity in the brains of subjects prevents or treats schizophrenia.
  • Each possibility represents a separate embodiment of the present invention.
  • the present invention provides a method for identifying a compound or composition useful for prophylactic or therapeutic treatment of a schizophrenia, comprising (a) contacting a first neuron with the compound or composition; (b) measuring a first activity of an ARTS protein in the first neuron; (c) contacting a second neuron with the compound or composition; (d) measuring a second activity of an ARTS protein in the second neuron; and (e) comparing the first activity with the second activity.
  • the first activity is altered relative to the second activity, then the compound or composition is useful for prophylactic or therapeutic treatment of the schizophrenia.
  • the neuron is a primary cell derived from the brain or CNS. In another embodiment, the neuron is from a neural cell line. In another embodiment, the neuron is any other type of neuron known in the art. Each possibility represents a separate embodiment of the present invention.
  • altered in another embodiment, refers to an increase in the activity. In another embodiment, “altered” refers to a decrease in the activity. In another embodiment, “altered” refers to an aberrant regulation or pattern of the activity. Each possibility represents a separate embodiment of the present invention.
  • the present invention provides a method for identifying a compound or composition useful for prophylactic or therapeutic treatment of a schizophrenia, comprising (a) contacting a first neuron with the compound or composition; (b) measuring a first expression of an ARTS protein in the first neuron; (c) contacting a second neuron with the compound or composition; (d) measuring a second expression of an ARTS protein in the second neuron; and (e) comparing the first expression with the second expression.
  • the first expression is altered relative to the second expression, then the compound or composition is useful for prophylactic or therapeutic treatment of the schizophrenia.
  • the present invention provides a method for testing a compound or composition for utility in prophylactic or therapeutic treatment of a schizophrenia, comprising determining whether the compound or composition disrupts a complex containing an ARTS protein and an IAP protein, whereby if the compound or composition disrupts the complex, then the compound or composition is useful for prophylactic or therapeutic treatment of the schizophrenia.
  • the subject of a method of the present invention is a male.
  • the brains of schizophrenic males exhibit lower levels of ARTS than brains of non- schizophrenic males (Example 3).
  • providing ARTS activity to brains of schizophrenic males alleviates the disease.
  • providing ARTS activity to brains of males prevents the onset of schizophrenia.
  • antagonizing ARTS activity in the brains of males prevents or treats schizophrenia.
  • antagonizing ARTS activity in the brains of males prevents or treats schizophrenia.
  • Each possibility represents a separate embodiment of the present invention.
  • the subject is an adult. In another embodiment, the subject is a female. In another embodiment, the subject is a child. In another embodiment, the subject is over about 25 years old. La another embodiment, the subject is over about 30 years old. In another embodiment, the subject is over about 35 years old. In another embodiment, the subject is over about 40 years old. In another embodiment, the subject is over about 50 years old. In another embodiment, the subject is over about 60 years old. In another embodiment, the subject is over about 70 years old. Each possibility represents a separate embodiment of the present invention.
  • the subject has a relatively high susceptibility to the disease, disorder, or symptom that is treated, prevented, or detected by a method of the present invention.
  • Methods of determining susceptibility to schizophrenia are well known in the art and are described, for example, in Hanson DR, BMC Med Genet. 2005 Feb 11;6(1):7. Each method represents a separate embodiment of the present invention.
  • the activity of an ARTS protein that is modulated or detected in a method of the present invention is an induction of apoptosis in the neuron.
  • the activity is enhancing sensitivity of the neuron to a pro-apoptotic stimulus.
  • the activity is binding to an IAP protein (United States Patent Application Serial No. 11/028,509, which is incorporated herein by reference).
  • the activity is inducing release of a caspase from an IAP protein.
  • the activity is induction of caspase activity.
  • the activity is reducing the level of an IAP protein.
  • the activity is inducing intracellular translocation of an IAP protein.
  • the activity of an ARTS protein that is modulated or detected is reducing the level of any other protein that is anti-apoptotic.
  • the activity of an ARTS protein is inhibiting an activity of any other protein that is anti-apoptotic.
  • the protein is surviving.
  • the protein is bcl2.
  • the protein is any other anti-apototic protein known in the art. Each possibility represents a separate embodiment of the present invention.
  • the activity is any other biological activity of ARTS protein.
  • ARTS protein any other biological activity of ARTS protein.
  • the IAP protein of methods and compositions of the present invention is an X-link inhibitor of apoptosis protein (XIAP) or a variant or homologue thereof.
  • XIAP X-link inhibitor of apoptosis protein
  • the IAP protein has the sequence set forth in SEQ ID No: 2.
  • the IAP protein has a sequence homologous to the sequence set forth in SEQ ID No: 2.
  • the IAP protein is a variant of the sequence set forth in SEQ ID No: 2.
  • the IAP protein is an isoform of the sequence set forth in SEQ ID No: 2:
  • the IAP protein is a CLAP protein.
  • the LAP protein is any other LAP protein known in the art. Each possibility represents a separate embodiment of the present invention.
  • “Dysregulated,” in another embodiment, refers to an aberrant increase. In another embodiment, the aberrant increase is a basal increase. In another embodiment, the aberrant increase is an increase in response to a trigger or stimulus. In another embodiment, “dysregulated” refers to an aberrant decrease. In another embodiment, the aberrant decrease is a basal decrease. In another embodiment, the aberrant decrease is a decrease in response to a trigger or stimulus. In another embodiment, “dysregulated” refers to an aberrant pattern of regulation. Each possibility represents a separate embodiment of the present invention.
  • Apoptosis refers, in another embodiment, to programmed cell death, hi another embodiment, “apoptosis” refers to process of cell suicide, in which the cell shrinks and cleaves its substrates of capsins. In another embodiment, “apoptosis” is defined by the presence of an indicator thereof.
  • Methods of measuring apoptosis include, e.g, the TUNEL assay (Example 4), morphological methods, e.g. detection of cytoplasmic vacuolization or plasma membrane blebbing (Jacquel A et al, FASEB J.
  • the neuron treated or tested by a method of the present invention is in the brain.
  • the neuron is in the frontal cortex.
  • the neuron is in the CNS.
  • the compound or composition that is administered in a method of the present invention comprises, in another embodiment, a nucleic acid encoding ARTS.
  • the compound or composition is an ARTS protein or a fragment thereof.
  • the compound or composition comprises an ARTS protein or a fragment thereof.
  • the compound or composition is a mimetic compound of an ARTS protein or a fragment thereof.
  • the compound or composition comprises a mimetic compound of an ARTS protein or a fragment thereof.
  • the compound or composition comprises a nucleotide molecule (e.g. an antisense nucleotide or a small inhibitory RNA (siRNA) that binds to a nucleotide encoding ARTS.
  • siRNA small inhibitory RNA
  • the compound or composition is a transcription factor that affects ARTS expression.
  • the compound or composition is any other compound or composition that modulates any activity or expression of an ARTS protein.
  • the compound or composition allosterically regulates ARTS activity.
  • the compound or composition affects translocation of ARTS to the nucleus.
  • the compound or composition affects intracellular degradation of ARTS protein.
  • the compound or composition interacts with a downstream target of ARTS; i.e. an IAP protein.
  • the compound or composition selectively binds to a complex containing an ARTS protein and an LAP protein.
  • the compound or composition inhibits the formation of such a complex.
  • the compound or composition disrupts such a complex.
  • the compound or composition affects the spontaneous apoptosis in the neuron.
  • the compound or composition affects susceptibility of the neuron to apoptosis induced by pro-apoptotic stimuli (e.g. TGF-beta).
  • pro-apoptotic stimuli e.g. TGF-beta
  • model building is used to design the mimetic compounds as described in one of the above references.
  • solubility of the mimetic compounds is optimized as described in one of the above references.
  • an ARTS mimetic compound of methods and compositions of the present invention exhibits an activity that can be performed by ARTS protein.
  • the ARTS mimetic compound inhibits an activity that can be performed by ARTS protein.
  • the ARTS mimetic compound binds to a protein that interacts with ARTS.
  • the ARTS mimetic compound affects a protein that interacts with
  • the ARTS mimetic compound acts a dominant negative inhibitor of an activity that can be performed by ARTS protein.
  • mimetic compounds that interact with a ligand of a protein often act as "dominant negatives," i.e. compounds that antagonize the activity of the protein that they resemble.
  • a mimetic compound binds to a downstream target of the protein it resembles, e.g. XIAP, without activating the signaling pathway ordinarily activated by the protein.
  • a mimetic compound of the present invention antagonizes the ability of
  • the mimetic compound antagonizes the ability of another protein to induce apoptosis via XIAP. In another embodiment, the mimetic compound antagonizes any other activity of ARTS.
  • the activity is an induction of apoptosis in a neuron.
  • the activity is enhancing sensitivity of the neuron to a pro-apoptotic stimulus.
  • the activity is binding to an IAP protein.
  • the activity is inducing release of a caspase from an IAP protein.
  • the activity is induction of caspase activity.
  • the activity is reducing the level of an IAP protein.
  • the activity is inducing intracellular translocation of an LAP protein.
  • the activity is any other biological activity of ARTS protein.
  • a mimetic compound is based on a minimal domain or region of an ARTS protein that exhibits biological activity (Example 6).
  • the biological activity is, in another embodiment, any biological activity of ARTS known in the art.
  • Biological activities of ARTS are described, for example, in United States Patent Application Serial No. 11/028,509.
  • the subset of ARTS fragments is generated by deletion mutagenesis. Methods of deletion mutagenesis are well known in the art, and are described, for example in (Henikoff S, Gene 28(3): 351-9, 1984; and Pues H et al, Nucleic Acids Research, 25 (6): 1303-1304, 1997). Each method of identifying a mimetic compound represents a separate embodiment of the present invention.
  • the mimetic compound is a peptide.
  • the mimetic compound is a constrained mimic of a region of ARTS that possesses biological function.
  • the constrained mimic is a cyclical peptide.
  • the mimetic compound is a monoclonal antibody (mAb) having as the complementary-determining region (cdr) a peptide corresponding in structure or sequence to a region of ARTS having biological function.
  • the mimetic compound is an mAb having as the cdr a peptide that binds to a region of a downstream target of ARTS (e.g. an IAP protein) that mediates binding with ARTS.
  • This mAb is, in another embodiment, designed rationally by identifying the peptide and replacing the cdr-encoding region of a gene for an mAb with the sequence encoding the peptide, hi another embodiment, the mAb is identified empirically by raising an mAb against the appropriate region of the ARTS downstream target.
  • the peptide contained in the cdr is then used, in another embodiment, as an ARTS mimetic.
  • the peptide contained in the cdr is used to design a non-peptide ARTS mimetic.
  • the mimetic compound is a non-peptide.
  • the non-peptide mimetic compound comprises amino acids linked by peptide bonds.
  • the non-peptide mimetic compound comprises amino acids linked by non-peptide bonds.
  • the non-peptide mimetic compound does not comprise amino acids.
  • Each "type of mimetic compound represents a separate embodiment of the present invention.
  • an affected neuron is contacted directly with the compound or composition.
  • the neuron is contacted indirectly, via contacting the subj ect with the compound or composition, whereafter the compound or composition reaches that neuron by any one of many biological processes, e.g. diffusion, active transport, or circulation through the blood, lymph, interstitial fluid, or any other biological fluid.
  • the step of contacting is performed ex vivo. Each possibility represents a separate embodiment of the present invention.
  • a method of the present invention modulates or detects an ARTS activity or expression in a brain cell other than a neuron.
  • the brain cell is a glial cell.
  • the brain cell is a Schwann's Cell.
  • the brain cell is a satellite cell, hi another embodiment, the brain cell is a microglial cell.
  • the brain cell is an oligodendroglial cell, hi another embodiment, the brain cell is an astroglial, hi another embodiment, the brain cell is any other type of brain cell known in the art.
  • a method of the present invention modulates or detects an ARTS activity or expression in a neuron not residing in the brain cell; e.g. a neuron in the spinal cord or the peripheiy. Each type of brain cell and neuron represents a separate embodiment of the present invention.
  • a protein or nucleotide utilized in a method of the present invention is homologous to a ARTS protein or nucleotide disclosed herein.
  • the terms "homology,” “homologous,” etc, when in reference to any protein or peptide, refer, in another embodiment, to a percentage of AA residues in the candidate sequence that are identical with the residues of a corresponding native polypeptide, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent homology, and not considering any conservative substitutions as part of the sequence identity. Methods and computer programs for the alignment are well known in the art.
  • Homology is, in another embodiment, determined by computer algorithm for sequence alignment, by methods well described in the art.
  • computer algorithm analysis of nucleic acid sequence homology can include the utilization of any number of software packages available, such as, for example, the BLAST, DOMAIN, BEAUTY (BLAST Enhanced Alignment Utility), GENPEPT and TREMBL packages.
  • “homology” refers to identity to SEQ ID No: 1 of greater than 70%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 72%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 75%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 78%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 80%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 82%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 83%.
  • “homology” refers to identity to SEQ ID No: 1 of greater than 85%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 87%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 88%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 90%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 92%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 93%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 95%.
  • “homology” refers to identity to SEQ ID No: 1 of greater than 96%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 97%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 98%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of greater than 99%. In another embodiment, “homology” refers to identity to SEQ ID No: 1 of 100%. Each possibility represents a separate embodiment of the present invention.
  • homology is determined via determination of candidate sequence hybridization, methods of which are well described in the art (See, for example, “Nucleic Acid Hybridization” Hames, B. D., and Higgins S. J., Eds. (1985); Sambrook et al., 2001, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, N. Y.; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N. Y).
  • methods of hybridization are carried out under moderate to stringent conditions, to the complement of a DNA encoding a native caspase peptide.
  • Hybridization conditions being, for example, overnight incubation at 42 0 C in a solution comprising: 10-20 % formamide, 5 X SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7. 6), 5 X Denhardt's solution, 10 % dextran sulfate, and 20 ⁇ g/ml denatured, sheared salmon sperm DNA.
  • nucleic acids or “nucleotide” refers to a string of at least two base-sugar-phosphate combinations.
  • the term includes, in one embodiment, DNA and RNA.
  • Nucleotides refers, in one embodiment, to the monomeric units of nucleic acid polymers.
  • RNA is, in one embodiment, in the form of a tRNA (transfer RNA), snRNA (small nuclear RNA), rRNA (ribosomal RNA), mRNA (messenger RNA), anti-sense RNA, small inhibitory RNA (siRNA), micro RNA (miRNA) and ribozymes.
  • DNA can be, in other embodiments, in form of plasmid DNA, viral DNA, linear DNA, or chromosomal DNA or derivatives of these groups.
  • these forms of DNA and RNA can be single, double, triple, or quadruple stranded.
  • the term also includes, in another embodiment, artificial nucleic acids that contain other types of backbones but the same bases.
  • the artificial nucleic acid is a PNA (peptide nucleic acid).
  • PNA contain peptide backbones and nucleotide bases and are able to bind, in one embodiment, to both DNA and RNA molecules.
  • the nucleotide is oxetane modified.
  • the nucleotide is modified by replacement of one or more phosphodiester bonds with a phosphorothioate bond.
  • the artificial nucleic acid contains any other variant of the phosphate backbone of native nucleic acids known in the art.
  • nucleic acids and PNA are known to those skilled in the art, and are described in, for example, Neilsen PE, Curr Opin Struct Biol 9:353-57; and Raz NK et al Biochem Biophys Res Commun. 297:1075-84.
  • the production and use of nucleic acids is known to those skilled in art and is described, for example, in Molecular Cloning, (2001), Sambrook and Russell, eds. and Methods in Enzymology: Methods for molecular cloning in eukaryotic cells (2003) Purchio and G. C. Fareed. Each nucleic acid derivative represents a separate embodiment of the present invention.
  • Protein and/or peptide homology for any AA sequence listed herein is determined, in another embodiment, by methods well described in the art, including immunoblot analysis, or via computer algorithm analysis of amino acid sequences, utilizing any of a number of software packages available, via established methods. Some of these packages include the FASTA, BLAST, MPsrch or Scanps packages, and, in another embodiment, employ the use of the Smith and Waterman algorithms, and/or global/local or BLOCKS alignments for analysis, for example. Each method of determining homology represents a separate embodiment of the present invention.
  • the present invention provides a kit comprising a reagent utilized in performing a method of the present invention.
  • the present invention provides a kit comprising a composition, tool, or instrument of the present invention.
  • the pharmaceutical composition containing the ARTS-modulating compound is, in another embodiment, administered to a subject by any method known to a person skilled in the art, such as parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intra- dermally, subcutaneously, intra-peritonealy, intra-ventricularly, intra-cranially, intra-vaginally or intra-tumorally.
  • the pharmaceutical composition is administered orally, and is thus formulated in a form suitable for oral administration, i.e. as a solid or a liquid preparation.
  • suitable solid oral formulations include tablets, capsules, pills, granules, pellets and the like.
  • Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like.
  • the active ingredient is formulated in a capsule.
  • the composition of the present invention comprises, in addition to the active compound and the inert carrier or diluent, a hard gelating capsule.
  • the composition includes one or more excipients known in the art.
  • the pharmaceutical composition is administered by intravenous, intra-arterial, or intra-muscular injection of a liquid preparation.
  • the pharmaceutical composition is administered topically to body surfaces and is thus formulated in a form suitable for topical administration.
  • the pharmaceutical composition is administered as a suppository, for example a rectal suppository or a urethral suppository.
  • the pharmaceutical composition is administered by subcutaneous implantation of a pellet.
  • the pellet provides for controlled release of active ingredient agent over a period of time.
  • the pharmaceutical composition is a controlled-release composition.
  • Controlled- or sustained-release compositions include, in another embodiment, formulation in lipophilic depots (e.g. fatty acids, waxes, oils).
  • the composition is an immediate-release composition, i.e. a composition in which all of the anti-estrogen compound is released immediately after administration.
  • the pharmaceutical composition is delivered in a controlled release system.
  • the delivery mechanism comprises intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump is used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al, N. Engl. J. Med. 321:574 (1989).
  • polymeric materials are used; e.g. in microspheres in or an implant, hi another embodiment, a controlled release system is placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose.
  • compositions that contain an active component for example by mixing, granulating, or tablet-forming processes, is well understood in the art.
  • the active therapeutic ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient.
  • the active agent is mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions.
  • the active agent is converted into a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other substances.
  • the methods of the present invention comprise administering an ARTS- modifying compound as the sole active ingredient.
  • the present invention provides methods that comprise administering the ARTS-modifying compound in combination with one or more therapeutic agents (e.g. anti-schizophrenia agents).
  • therapeutic agents e.g. anti-schizophrenia agents.
  • ARTS protein levels in 58 frontal cortex paraffin fixed brain sections were analyzed. The samples were taken from 15 schizophrenic patients, 15 bipolar disorder patients, 14 major depression and 14 normal control subjects.
  • ARTS immuno- histochemical staining of normal brains revealed a homogeneous and intense ARTS immuno- reactivity in neuronal cell bodies and axons ( Figures IA-C). While staining of axons was similar in all samples and served as an internal control, a striking difference in ARTS expression in neuronal cell bodies was observed among the various groups. Only 33.3 % ⁇ 12.5% of the schizophrenic patient samples exhibited neuronal cell body ARTS immunoreactivi ⁇ y, compared to 87% (STE ⁇
  • ARTS-positive samples were divided into two categories: strong cell body staining and weak neuronal staining, and the percentage of non-reactive, weak-staining, and strong-staining brains in each groups plotted. Almost all of the schizophrenic samples (14 out of 15; 93.2%) exhibited no or weak ARTS neuronal cell body immuno-reactivity (Figure IE). In contrast, among the major depression samples, which represented the average levels of ARTS staining in the other diagnostic groups, only 35.6% of the samples exhibited none or weak cell body staining (Figure IF).
  • Frozen sections were homogenized using a Dounce tissue homogenizer and lysed with 300 ⁇ l of lysis buffer (50 mM Tris pH-8.0, 5 mM EDTA, 150 mM NaCl, 0.5% NP-40 protease inhibitors
  • RNA levels were quantitated using RT-PCR.
  • Total RNA was extracted from frontal cortex frozen samples using a Qiagen extraction kit.
  • cDNA was synthesized from the RNA samples, using random primers and AMV Reverse Transcriptase (Promega).400 ng of the resulting cDNA samples were used as PCR templates.
  • ARTS and beta actin were quantitated in each sample, and the ratio of the amounts calculated.
  • the primers used to amplify ARTS were: 5' primer: 5'-AGA GAG GAT CAT GCA AAC TGT-3' (SEQ ID No: 3).
  • 3' primer 5'-CTC TTG GCC TGT TCC CTT G-3' (SEQ ID No: 4).
  • Primers used to amplify beta-actin were: 5' primer: 5'-CAA CGG CTC CGG CAT GTG-3' (SEQ ID No: 5). 3' primer: 5'-CTC CTT AAT GTC ACG CAC GA-3' (SEQ ID No: 6).
  • ARTS protein is deficient in schizophrenic brains relative to normal brains.
  • ARTS levels in males of all other diagnostic groups exhibited the opposite pattern, being consistently higher than their levels in women of the same group. No significant difference was observed hi ARTS staining among female samples across the four diagnostic groups (Figure 3).
  • ARTS protein is deficient in schizophrenic male brains relative to normal male brains.
  • TUNEL Terminal deoxynucleotidyl transferase Biotin-dUTP Nick End Labeling POD assay
  • the CNS catecholaminergic CAD cell line was provided by Cogent Neuroscience. Cells were grown in Dulbecco ' s modified Eagle F- 12 medium (DMED-F 12 ; Biological Industries, Israel) with 4.5 grams per liter (g/L) D-glucose, 8% fetal calf serum (FCS), penicillin (100 units per milliliter [U/ml]), streptomycin (100 micrograms ( ⁇ g)/ml) and glutamine (2 millimolar [mM]). The cells were grown at 37° C in a 5% CO 2 atmosphere.
  • DMED-F 12 Dulbecco ' s modified Eagle F- 12 medium
  • FCS fetal calf serum
  • penicillin 100 units per milliliter [U/ml]
  • streptomycin 100 micrograms ( ⁇ g)/ml)
  • glutamine 2 millimolar [mM]
  • CAD cells CNS catecholaminergic cell line
  • dCAD cells were transfected with either pEF 1 - AU5 -ARTS expression vector or pEF 1 - AU5 empty vector (negative control), and levels of active caspase 3, reflecting the apoptosis rate, were measured in the transfected dCAD cells.
  • a three-fold increase in caspase 3 activity was observed in the transfected cells, which expressed high levels of ARTS ( Figure 5D).
  • ARTS plays a role in pathological processes occurring in the neurons of schizophrenic patients.
  • the ARTS C terminus was shown to be sufficient for induction of apoptosis, and was thus further divided to define its regions with biological activity.
  • Three fragments, pepl , pep2, and pep3 were shown to penetrate cells using fluorescence of Fluorescein- labeled peptides. To determine whether these fragments were sufficient to induce apoptosis, they were added to the media of K562 cells (an erythroleukemia cell line derived from a chronic myeloid leukemia patient in blast crisis).
  • the third peptide (residues 19-27) showed significant pro-apoptotic activity, while the second peptide (residues 10-18) showed lesser, but detectable, activity (Figure 6).
  • the ARTS C terminus and fragments thereof are capable of inducing apoptosis in cells.
  • the biologically active region of ARTS was used as the basis for generation of an ARTS mimetic compound.
  • the mimetic compound corresponded to residues 19-27 of the ARTS C terminus, but contained D-glutamine in place of L-glutamine.
  • the mimetic was added to 2 different cell lines, Jurkat cells (ALL, or acute lymphoblastic leukemia) and ARH-77 cells (a multiple myeloma line) at a concentration of 100 mcM for 48 hours, and apoptosis was measured. As depicted in Table 1, the mimetic induced apoptosis in both cell lines.
  • the ARTS protein non-peptide mimetic obtained from Example 7, or other ARTS mimetics with apoptosis-inducing activity is tested for ability to treat a schizophrenic disorder or psychotic symptom in an animal model, such as a model described in Joober R et al, J Psychiatry Neurosci. 2002 Sep;27(5):336-47.
  • the mimetic is also tested for ability to prevent or reduce the incidence of schizophrenia in the animal model.
  • the ARTS protein non-peptide mimetic is tested for ability to treat a schizophrenic disorder in humans. Additional, the mimetic is tested for ability to prevent a schizophrenic disorder in subjects with a family history of the disorder, or to prevent recurrence of the disorder in subject with previously afflicted by it.
  • DNA samples are obtained from schizophrenic and normal samples, and the coding sequence and promoter and regulatory sequences of ARTS determined. Correlation of particular polymorphisms or haplotypes with the presence of schizophrenia is assessed using a statistical method such as Classification and Regression Tree software (CART). Polymorphisms or haplotypes identified are then tested in independent samples as indicators of schizophrenia, and in prospective studies as predictors or development of schizophrenia.
  • CART Classification and Regression Tree software

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Abstract

L'invention concerne des méthodes pour traiter ou pour réduire un cas de maladie, de trouble, ou un symptôme chez un patient. La maladie, le trouble ou le symptôme susmentionné comprenne: l'apoptose dérégulée d'un neurone. La méthode de l'invention consiste à mettre en contact le patient avec un composé ou une composition qui modifie une activité ou une expression d'une protéine ARTS (protéine associée à l'apoptose dans la voie de signalisation TGF-ß). Cette invention concerne également des méthodes pour déterminer une prédisposition ou un risque, chez un patient, par rapport à la maladie, le trouble ou au symptôme susmentionné, ainsi que des méthodes pour identifier un composé ou une composition utile pour un traitement prophylactique ou thérapeutique de la schizophrénie, ces méthodes consistant à détecter une activité ou une expression de la protéine ARTS ou à déterminer une séquence d'un gène codant une protéine ARTS.
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