WO2004079371A1 - Diagnosis of autism - Google Patents

Diagnosis of autism Download PDF

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Publication number
WO2004079371A1
WO2004079371A1 PCT/SE2004/000193 SE2004000193W WO2004079371A1 WO 2004079371 A1 WO2004079371 A1 WO 2004079371A1 SE 2004000193 W SE2004000193 W SE 2004000193W WO 2004079371 A1 WO2004079371 A1 WO 2004079371A1
Authority
WO
WIPO (PCT)
Prior art keywords
peptides
autism
seq
sample
determined
Prior art date
Application number
PCT/SE2004/000193
Other languages
French (fr)
Inventor
Naghi Momeni
Anders Grubb
Original Assignee
Forskarpatent I Syd Ab
Anders Grubb
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP04716392A priority Critical patent/EP1608982B9/en
Application filed by Forskarpatent I Syd Ab, Anders Grubb filed Critical Forskarpatent I Syd Ab
Priority to DE602004008439T priority patent/DE602004008439T2/en
Priority to CA2518066A priority patent/CA2518066C/en
Priority to DK04716392T priority patent/DK1608982T3/en
Priority to AU2004217571A priority patent/AU2004217571B2/en
Priority to NZ542149A priority patent/NZ542149A/en
Priority to PL04716392T priority patent/PL1608982T3/en
Priority to BRPI0408067-0A priority patent/BRPI0408067A/en
Priority to CN2004800058238A priority patent/CN1795386B/en
Priority to JP2006507920A priority patent/JP4452715B2/en
Priority to KR1020057016254A priority patent/KR101096487B1/en
Publication of WO2004079371A1 publication Critical patent/WO2004079371A1/en
Priority to US13/166,143 priority patent/US8268576B2/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease

Definitions

  • the present invention relates to a method for diagnosis of autism by means of a simple test on a sample of a subject.
  • Autism is the term for a symptom-complex of a subject meaning such a bad communication possibility with people around that the subject in question has to be taken care of by the society in different ways during its whole lifetime.
  • the pathophysiology of autism involves abnormal communication between neurons, possibly associated with abnormal patterns peptides, e.g., neuropeptides in the brain.
  • Abnormal levels of peptides might be revealed by proteomic studies of proteins/peptides below 10 kDa in spinal fluid and/or blood plasma. Detection of abnormal levels of peptides in autism will allow generation of new hypotheses concerning its pathophysiology and might facilitate diagnostics and suggest new treatment possibilities. Since most peptides are generated by proteolysis of larger precursor molecules abnormal levels of peptides might be caused by abnormal proteolytic activity.
  • EP-A-0 979 828 discloses a method for diagnosing autism by determining specific peptides present in a biological fluid.
  • the peptides which comprises 3 to 4 amino acids are said to indicate autism when present in high amounts.
  • EP-A-0 969 015 relates to a method for diagnosing a disease, such as autism, by identifying peptides present in a tissue of body liquid.
  • the peptides are disclosed as having a length of 3 to 8 amino acids, and having a molecular weight of ⁇ 1081.
  • the amount of oxytocin-extened (OT-X) is higher in autistic patients, while the amount of oxytocin (9 amino acids) is lower.
  • US-A-2002/0006640 relates polypeptides and methods for diagnosis of inter alia autism.
  • the present invention is based on a hypothesis that the basis of autism is the presence of an abnormal peptide pattern in the brain and/or the fluids penetrating or surrounding the brain, i.e., blood and cerebrospinal fluid, and that some of these peptides might disturb the signals (e.g., carried neuropeptides), used by the brain for communication.
  • the invention is characterized in the determination of the presence or absence of certain proteins/peptides with specific amino acids sequences, present in a body sample, which proteins/peptides have the molecular masses of 1779 +/- 1 Da, 1865 +/- 1 Da and 2022 +/- 1 Da, respectively.
  • the present invention relates to determining in a tissue sample, body liquid and/or plasma sample a higher than normal level of one or more of the following peptides
  • the amount of the peptide(s) is more than 10 times that present in a sample of a healthy subject.
  • the respective peptide is determined using ELISA technology.
  • the respective peptide is determined using RIA technology.
  • the respective peptide is determined using a SELDI-TOF-MS system.
  • kits for determining said peptides whereby the kit comprises a marker for certain peptides having the molecular weights 1779, 1865 and 2022, respectively.
  • it comprises a marker for one or more of the peptides encoded for by the amino acid sequence SSKITHRIHWESASLLR, SSKITHRIHWESASLL, and/or SKITHRIHWESASLL.
  • Body liquid means herein any body liquid such as blood, blood serum, blood plasma, spinal fluid, cerebrospinal fluid, and lymph.
  • the present peptides may be a fragment of a plasma protein called complementary factor C3.
  • FIG. 1 shows eight different mass spectrometry profiles in the 1700 to 2200 Dalton band obtained from eight individuals, four without a diagnosis of autism and four diagnosed as autistic children.
  • the upper four are mass spectrometry bands from the individuals without a diagnosis of autism, and the lower four are from the autistic children. It is apparent that there are at least three different peaks appearing in the samples of the autistic children that differ considerably from those of children without a diagnosis of autism.
  • appropriate molecular mass markers it is determined that at about 1779, 1865 and 2022 Daltons there are significant peaks present.
  • the different peak areas represent amounts of the respective peptide present which amounts are more than ten times higher in samples from autistic children than in samples from children without a diagnosis of autism.
  • the structures of the peptides were determined using MS/MS mass spectrometry, whereby their amino acid sequences were determined to be SSKITHRIHWESASLLR (SEQ. ID. NO. 1), SSKITHRIHWESASLL (SEQ. ID. NO. 3), and SKITHRIHWESASLL (SEQ. ID. NO. 3), respectively.
  • the first peptide is known as complement C3f (NCBI accession number 1413205A), the second one lacks C-terminal arginine, and the third one further lacks N-terminal serine.
  • concentrations of the selected peptides in e.g., plasma or spinal fluid samples can easily be determined by means of immunochemical techniques, such as ELISA or RIA.
  • Antibodies will be used and labelling of antibodies and/or the antigen peptides will be performed according to general protocols using e.g., the chloramine T method for radiolabelling.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Neurology (AREA)
  • Genetics & Genomics (AREA)
  • Microbiology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Peptides Or Proteins (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
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Abstract

The present invention relates to a method for diagnosing autism by determining the presence of high concentrations of certain peptides analysing a tissue sample, a body liquid sample and/or a plasma sample with regard to the presence of certain peptides having the amino acid sequences SKITHRIHWESASLL, SSKITHRIHWESASLL, and SSKITHRIHWESASLLR with the molecular masses 1779 +/- 1 Da, 1865 +/-1 Da and 2022+/-1 Da, respectively.

Description

TITLE
DIAGNOSIS OF AUTISM
DESCRIPTION
Technical field
The present invention relates to a method for diagnosis of autism by means of a simple test on a sample of a subject.
Background of the invention
Autism is the term for a symptom-complex of a subject meaning such a bad communication possibility with people around that the subject in question has to be taken care of by the society in different ways during its whole lifetime.
One to five out of 1000 persons born in Sweden suffer from autism. The diagnosis is difficult to establish and can take several years to secure. The pedagogical and social measures, which the society and the family of the autistic person have to take, are lifelong and extremely costly. The suffering of the ones affected and their families is great. No biochemical treatment is known (e.g., use of pharmaceuticals) so far.
The pathophysiology of autism involves abnormal communication between neurons, possibly associated with abnormal patterns peptides, e.g., neuropeptides in the brain. Abnormal levels of peptides might be revealed by proteomic studies of proteins/peptides below 10 kDa in spinal fluid and/or blood plasma. Detection of abnormal levels of peptides in autism will allow generation of new hypotheses concerning its pathophysiology and might facilitate diagnostics and suggest new treatment possibilities. Since most peptides are generated by proteolysis of larger precursor molecules abnormal levels of peptides might be caused by abnormal proteolytic activity.
There is very little biochemical research done and available concerning autism as there are no animal models available and there is a practical problem collecting a more substantive patient material.
In the prior art EP-A-0 979 828 discloses a method for diagnosing autism by determining specific peptides present in a biological fluid. The peptides which comprises 3 to 4 amino acids are said to indicate autism when present in high amounts. EP-A-0 969 015 relates to a method for diagnosing a disease, such as autism, by identifying peptides present in a tissue of body liquid. The peptides are disclosed as having a length of 3 to 8 amino acids, and having a molecular weight of < 1081.
Green, L. A. et al in Biological Psychiatry, 50: 609-613 (2001) discloses that the oxytocin concentration in plasma of autistic persons is different from the one in healthy persons. The amount of oxytocin-extened (OT-X) is higher in autistic patients, while the amount of oxytocin (9 amino acids) is lower.
US-A-2002/0006640 relates polypeptides and methods for diagnosis of inter alia autism.
None of these documents discloses the peptides of the present invention.
Summary of the present invention The present invention is based on a hypothesis that the basis of autism is the presence of an abnormal peptide pattern in the brain and/or the fluids penetrating or surrounding the brain, i.e., blood and cerebrospinal fluid, and that some of these peptides might disturb the signals (e.g., carried neuropeptides), used by the brain for communication.
The invention is characterized in the determination of the presence or absence of certain proteins/peptides with specific amino acids sequences, present in a body sample, which proteins/peptides have the molecular masses of 1779 +/- 1 Da, 1865 +/- 1 Da and 2022 +/- 1 Da, respectively.
In particular the present invention relates to determining in a tissue sample, body liquid and/or plasma sample a higher than normal level of one or more of the following peptides
SKITHRIHWESASLL (SEQ. ID. NO. 1)
SSKITHRIHWESASLL (SEQ. ID. NO. 2)
SSKITHRIHWESASLLR (SEQ. ID. NO. 3)
In a preferred embodiment of the method, the amount of the peptide(s) is more than 10 times that present in a sample of a healthy subject. In a further preferred embodiment, the respective peptide is determined using ELISA technology.
In another preferred embodiment, the respective peptide is determined using RIA technology.
In a further other preferred embodiment, the respective peptide is determined using a SELDI-TOF-MS system.
In a further aspect of the invention it relates to a kit for determining said peptides, whereby the kit comprises a marker for certain peptides having the molecular weights 1779, 1865 and 2022, respectively.
In a preferred embodiment thereof, it comprises a marker for one or more of the peptides encoded for by the amino acid sequence SSKITHRIHWESASLLR, SSKITHRIHWESASLL, and/or SKITHRIHWESASLL.
Body liquid means herein any body liquid such as blood, blood serum, blood plasma, spinal fluid, cerebrospinal fluid, and lymph.
The present peptides, specifically identified above, may be a fragment of a plasma protein called complementary factor C3.
Detailed description of the present invention The present invention has been confirmed in a pilot study using a so-called SELDI-TOF- MS (Ciphergen Biosystems Inc. Palo Alto, CA. USA) technology, a new proteomics technology, whereby the peptide patterns of blood plasma of four autistic children and four non-autistic children were analysed and compared. Thereby it was found that at least three peptides, each containing 15 to 20 amino acids, were over represented in all autistic children in the molecular band 1700 to 2200 Dalton. Thereby the amount of said peptides were at least 10 times higher in the blood plasma of the autistic children compared to non-autistic children.
FIG. 1 shows eight different mass spectrometry profiles in the 1700 to 2200 Dalton band obtained from eight individuals, four without a diagnosis of autism and four diagnosed as autistic children. The upper four are mass spectrometry bands from the individuals without a diagnosis of autism, and the lower four are from the autistic children. It is apparent that there are at least three different peaks appearing in the samples of the autistic children that differ considerably from those of children without a diagnosis of autism. When using appropriate molecular mass markers it is determined that at about 1779, 1865 and 2022 Daltons there are significant peaks present. The different peak areas represent amounts of the respective peptide present which amounts are more than ten times higher in samples from autistic children than in samples from children without a diagnosis of autism.
The structures of the peptides were determined using MS/MS mass spectrometry, whereby their amino acid sequences were determined to be SSKITHRIHWESASLLR (SEQ. ID. NO. 1), SSKITHRIHWESASLL (SEQ. ID. NO. 3), and SKITHRIHWESASLL (SEQ. ID. NO. 3), respectively. The first peptide is known as complement C3f (NCBI accession number 1413205A), the second one lacks C-terminal arginine, and the third one further lacks N-terminal serine.
The concentrations of the selected peptides in e.g., plasma or spinal fluid samples can easily be determined by means of immunochemical techniques, such as ELISA or RIA. Antibodies will be used and labelling of antibodies and/or the antigen peptides will be performed according to general protocols using e.g., the chloramine T method for radiolabelling.
It is apparent that high levels in body fluids/tissue of these peptides identified above are at least markers of an autistic condition and can readily be used to diagnose autism. However, the determination of the presence of these peptides in high levels also means that a possible pathogenic mechanism of autism has been discovered and that this might lead to new possibilities of treatment of autism, e.g., by suppressing the formation of these peptides.

Claims

1. Method for diagnosing autism in subjects suspected of suffering of autism by analysing a tissue sample, a body liquid sample and/or a plasma sample with regard to the presence of high concentrations of certain peptides having the molecular masses 1779 +/- 1 Da, 1865 +/- 1 Da and 2022 +/- 1 Da, respectively.
2. Method according to claim 1, wherein the amino acid sequences of the peptides are
SKITHRIHWESASLL (SEQ. ID. NO. 1)
SSKITHRIHWESASLL, and/or (SEQ. ID. NO. 2)
SSKITHRIHWESASLLR (SEQ. ID. NO. 3)
3. Method according to claim 1, wherein the amount of the peptide(s) is more than 10 times that present in a sample of a non-autistic subject.
4. Method according to claims 1-3, wherein any quantitative immunochemical method is used.
5. Method according to claims 1-3, wherein the respective peptide is determined using ELISA technology.
6. Method according to claims 1-3, wherein the respective peptide is determined using RIA technology.
7. Method according to claims 1-3, wherein the respective peptide is determined using a SELDI-TOF-MS system.
8. Kit comprising a marker for certain peptides having the molecular masses 1779 +/-1 Da, 1865 +/-1 Da and 2022 +/-1 Da, respectively. Kit according to claim 8, wherein it comprises a marker for one or more of the peptides having the amino acid sequences
SKITHRIHWESASLL (SEQ. ID. NO. 1)
SSKITHRIHWESASLL, and/or (SEQ. ID. NO. 2)
SSKITHRIHWESASLLR. (SEQ. ID. NO. 3)
PCT/SE2004/000193 2003-03-04 2004-03-02 Diagnosis of autism WO2004079371A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
NZ542149A NZ542149A (en) 2003-03-04 2004-03-02 Diagnosis of autism by determining the presence or absence of certain proteins/peptides with specific amino acids sequences that have molecular masses of 1779 +/-1 Da, 1865+/-1 Da and 2022+/-1 Da, respectively
DE602004008439T DE602004008439T2 (en) 2003-03-04 2004-03-02 DIAGNOSIS OF AUTISM
CA2518066A CA2518066C (en) 2003-03-04 2004-03-02 Diagnosis of autism
DK04716392T DK1608982T3 (en) 2003-03-04 2004-03-02 Diagnosis of autism
AU2004217571A AU2004217571B2 (en) 2003-03-04 2004-03-02 Diagnosis of autism
EP04716392A EP1608982B9 (en) 2003-03-04 2004-03-02 Diagnosis of autism
PL04716392T PL1608982T3 (en) 2003-03-04 2004-03-02 Diagnosis of autism
JP2006507920A JP4452715B2 (en) 2003-03-04 2004-03-02 Methods of using specific peptides as indicators of autism
CN2004800058238A CN1795386B (en) 2003-03-04 2004-03-02 Diagnosis of autism
BRPI0408067-0A BRPI0408067A (en) 2003-03-04 2004-03-02 autism diagnosis
KR1020057016254A KR101096487B1 (en) 2003-03-04 2004-03-02 Diagnosis of autism
US13/166,143 US8268576B2 (en) 2003-03-04 2011-06-22 Diagnosis of autism

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0300586A SE0300586L (en) 2003-03-04 2003-03-04 Diagnosis of autism
SE0300586-5 2003-03-04

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US54810004A A-371-Of-International 2003-03-04 2004-03-02
US13/166,143 Continuation US8268576B2 (en) 2003-03-04 2011-06-22 Diagnosis of autism

Publications (1)

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WO2004079371A1 true WO2004079371A1 (en) 2004-09-16

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PCT/SE2004/000193 WO2004079371A1 (en) 2003-03-04 2004-03-02 Diagnosis of autism

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US (1) US8268576B2 (en)
EP (1) EP1608982B9 (en)
JP (1) JP4452715B2 (en)
KR (1) KR101096487B1 (en)
CN (1) CN1795386B (en)
AT (1) ATE371192T1 (en)
AU (1) AU2004217571B2 (en)
BR (1) BRPI0408067A (en)
CA (1) CA2518066C (en)
DE (1) DE602004008439T2 (en)
DK (1) DK1608982T3 (en)
ES (1) ES2293234T3 (en)
NZ (1) NZ542149A (en)
PL (1) PL1608982T3 (en)
PT (1) PT1608982E (en)
RU (1) RU2340900C2 (en)
SE (1) SE0300586L (en)
WO (1) WO2004079371A1 (en)
ZA (1) ZA200507082B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012082056A1 (en) 2010-12-16 2012-06-21 Autism Biodiagnosis Ltd. Novel biomarker and uses thereof in diagnosis, treatment of autism
US9770423B2 (en) 2012-07-22 2017-09-26 Indiana University Research And Technology Corporation Modulation sAPP, sAAPα and BDNF levels in individuals diagnosed with FXS and ASD
US10634677B2 (en) 2013-10-14 2020-04-28 Indiana University Research And Technology Corporation Use of acamprosate to modulate ERK1/2 activation in animal models for FXS and ASD and individuals diagnosed with FXS and ASD

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4677556B2 (en) * 2005-04-22 2011-04-27 国立大学法人 千葉大学 Diagnostic agent for autism
JP5306345B2 (en) * 2007-07-26 2013-10-02 フェノメノーム ディスカバリーズ インク Methods for diagnosing, assessing risk and monitoring autism spectrum disorders
CN105652016A (en) * 2016-01-28 2016-06-08 深圳大学 Autism detection marker and detection method thereof
EP3594687A1 (en) 2017-03-10 2020-01-15 Sphingo Brain Co., Ltd. Method for diagnosing psychiatric disorders
US11131681B2 (en) * 2017-03-10 2021-09-28 Dr. Raymond Laboratories, Inc. Method for diagnosing psychiatric disorders
RU2643760C1 (en) * 2017-08-07 2018-02-05 Федеральное государственное бюджетное научное учреждение "Научный центр психического здоровья" Method of determining the necessity of using psycho pharmacotherapy among the patients with disorders of autist spectrum at the moment of their examination
KR20190106442A (en) 2018-03-09 2019-09-18 스핑고브레인 주식회사 Method for diagnosing psychiatric disorders using vernix caseosa, amniotic fluid or cord blood

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0969015A2 (en) * 1998-06-15 2000-01-05 Ortho-Clinical Diagnostics, Inc. Peptide diagnostic markers for human disorders
EP0979828A1 (en) * 1998-08-04 2000-02-16 Radim S.p.A. A method for the diagnosis of autism
US20020006640A1 (en) * 1999-11-04 2002-01-17 Jian Ni Uteroglobin-like polynucleotides, polypeptides, and antibodies

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Publication number Priority date Publication date Assignee Title
US6998243B2 (en) 2001-04-30 2006-02-14 Syn X Pharma, Inc. Biopolymer marker indicative of disease state having a molecular weight of 1793 daltons

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0969015A2 (en) * 1998-06-15 2000-01-05 Ortho-Clinical Diagnostics, Inc. Peptide diagnostic markers for human disorders
EP0979828A1 (en) * 1998-08-04 2000-02-16 Radim S.p.A. A method for the diagnosis of autism
US20020006640A1 (en) * 1999-11-04 2002-01-17 Jian Ni Uteroglobin-like polynucleotides, polypeptides, and antibodies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GREEN L.A. ET AL.: "Oxytocin and Autistic Disorsder: Alterations in Peptide Forms", BIOLOGICAL PSYCHIATRY, vol. 50, 2001, pages 609 - 613, XP002980034 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012082056A1 (en) 2010-12-16 2012-06-21 Autism Biodiagnosis Ltd. Novel biomarker and uses thereof in diagnosis, treatment of autism
CN103328501A (en) * 2010-12-16 2013-09-25 奥蒂斯姆生物技术有限公司 Novel biomarker and uses thereof in diagnosis, treatment of autism
US9347956B2 (en) 2010-12-16 2016-05-24 Autism Biotech Limited Biomarker and uses thereof in diagnosis, treatment of autism
US9770423B2 (en) 2012-07-22 2017-09-26 Indiana University Research And Technology Corporation Modulation sAPP, sAAPα and BDNF levels in individuals diagnosed with FXS and ASD
US10634677B2 (en) 2013-10-14 2020-04-28 Indiana University Research And Technology Corporation Use of acamprosate to modulate ERK1/2 activation in animal models for FXS and ASD and individuals diagnosed with FXS and ASD
US11733243B2 (en) 2013-10-14 2023-08-22 Indiana University Research And Technology Corporation Use of acamprosate to modulate ERK1/2 activation in animal models for FXS and ASD and individuals diagnosed with FXS and ASD

Also Published As

Publication number Publication date
US8268576B2 (en) 2012-09-18
CN1795386B (en) 2010-08-25
RU2005130641A (en) 2006-02-10
KR20060006774A (en) 2006-01-19
CN1795386A (en) 2006-06-28
PL1608982T3 (en) 2008-01-31
BRPI0408067A (en) 2006-02-14
US20120149038A1 (en) 2012-06-14
DE602004008439T2 (en) 2008-05-21
SE0300586L (en) 2004-09-05
RU2340900C2 (en) 2008-12-10
CA2518066A1 (en) 2004-09-16
PT1608982E (en) 2007-11-09
EP1608982B9 (en) 2008-07-23
EP1608982A1 (en) 2005-12-28
JP4452715B2 (en) 2010-04-21
JP2006519391A (en) 2006-08-24
AU2004217571A1 (en) 2004-09-16
ATE371192T1 (en) 2007-09-15
DE602004008439D1 (en) 2007-10-04
ES2293234T3 (en) 2008-03-16
DK1608982T3 (en) 2007-11-26
ZA200507082B (en) 2007-02-28
AU2004217571B2 (en) 2009-03-12
CA2518066C (en) 2011-05-10
NZ542149A (en) 2008-03-28
SE0300586D0 (en) 2003-03-04
EP1608982B1 (en) 2007-08-22
KR101096487B1 (en) 2011-12-20

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