Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-08-11
2002-10-01
Kunz, Gary L. (Department: 1647)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C530S399000, C530S350000, C514S002600, C514S012200
Reexamination Certificate
active
06458541
ABSTRACT:
BACKGROUND OF THE INVENTION
Modem psychiatry typically subdivides mood disorders into bipolar disorders (episodes of mania or both mania and depression) and unipolar depressive disorder (episodes of depression). Symptoms of mania include expansive, elevated or irritable mood, inflated self-esteem, grandiosity, decreased need for sleep, increased talkativeness, racing thoughts, distractibility, increased goal-directed activity, and excessive involvement in pleasurable activities with a high potential for painful consequences. Depressive symptoms include depressed mood, diminished interest or pleasure in activities, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness, excessive guilt, inability to concentrate or act decisively, and recurrent thoughts of death or suicide. Several mental disorders have been proposed as alternate expressions of a bipolar genotype, including variants of schizoaffective disorder, recurrent unipolar depression and hypomania (bipolar II disorder).
Neuropsychiatric disorders, such as schizophrenia, attention deficit disorders, schizoaffective disorders, bipolar disorders and unipolar disorders, differ from neurological disorders in that anatomical or biochemical pathologies are readily detectable for the latter but not the former. Largely as a result of this difference, drugs which have been used to treat individuals with neuropsychiatric disorders, including lithium salts, valproic acid and carbamazepine, have not been predictably effective in treatment regimens across a variety of patients. Treatment regimens are further complicated by the fact that clinical diagnosis currently relies on clinical observation and subjective reports. Identification of the anatomical or biochemical defects which result in neuropsychiatric disorders is needed in order to effectively distinguish between the disorders and to allow the design and administration of effective therapeutics for these disorders.
SUMMARY OF THE INVENTION
As described herein, it has been discovered that a polymorphism in the gene for brain-derived neurotrophic factor (BDNF) is negatively correlated with incidence of neuropsychiatric disorders (e.g., bipolar disorder). In particular, it has been discovered that one or more single nucleotide polymorphisms within the nucleotide sequence encoding the 132 amino acid prepro portion of the BDNF gene product is correlated with reduced incidence of bipolar disorder in a sample population assessed as described herein. In one embodiment, a single nucleotide polymorphism from G to A at nucleotide position 424, resulting in an amino acid change from valine to methionine at amino acid position −63 (relative to the start of the mature protein), is correlated with a reduced incidence of bipolar disorder in the sample population assessed as described herein. That is, it has been determined that there is a variation from random (i.e., that which would be expected by chance) in the transmission of the reference (G) and variant (A) alleles from a parent who is heterozygous for the BDNF alleles to an offspring diagnosed with bipolar disorder. The variant allele (A) is transmitted less frequently (34 of 98 times) to the bipolar offspring than would be expected by chance, while the reference allele (G) is transmitted more frequently (64 of 98 times) than would be expected by chance (p=0.004). Thus, it appears that the variant allele may contribute to protection or reduction in symptomology with respect to bipolar disorder. Alternatively, this particular polymorphism may be one of a group of two or more polymorphisms in the BDNF gene which contributes to the presence, absence or severity of the neuropsychiatric disorder, e.g., bipolar disorder.
Accordingly, the invention relates to methods for diagnosing and treating neuropsychiatric disorders, especially bipolar disorder, and to methods for identifying compounds for use in the diagnosis and treatment of neuropsychiatric disorders. The invention relates to novel compounds and pharmaceutical compositions for use in the diagnosis and treatment of neuropsychiatric disorders. The invention further relates to kits for use in diagnosing neuropsychiatric disorders. In a preferred embodiment, the neuropsychiatric disorder is bipolar disorder.
In one embodiment, the invention relates to a method for predicting the likelihood that an individual will have a neuropsychiatric disorder (or aiding in the diagnosis of a neuropsychiatric disorder), e.g., bipolar disorder, comprising the steps of obtaining a DNA sample from an individual to be assessed and determining the nucleotide present at nucleotide position 424 of the BDNF gene. The presence of an “A” (the variant nucleotide) at position 424 indicates that the individual has a lower likelihood of having a neuropsychiatric disorder than an individual having a “G” at that position, or a greater likelihood of having less severe symptomology. In a preferred embodiment, the neuropsychiatric disorder is bipolar disorder. In a particular embodiment, the individual is an individual at risk for development of bipolar disorder.
In another embodiment, the invention relates to pharmaceutical compositions comprising a variant BDNF gene product for use in the treatment of neuropsychiatric disorders. In one embodiment, the gene product is a peptide comprising amino acids −1 through −132, or a functional portion thereof, of a variant BDNF gene product for use in the treatment of neuropsychiatric disorders. The invention further relates to the use of compositions (i.e., agonists and antagonists) which enhance or increase or which reduce or decrease, respectively, the activity of a peptide comprising amino acids −1 through −132, or a functional portion thereof, of a variant BDNF gene product for use in the treatment of neuropsychiatric disorders. The invention also relates to the use of a nucleic acid molecule encoding a variant BDNF gene product for use in the treatment of neuropsychiatric disorders. In one embodiment, the gene product is a peptide comprising amino acids −1 through −132, or a functional portion thereof, of a variant BDNF gene product. In a particular embodiment the neuropsychiatric disorder is bipolar disorder.
In another embodiment, the invention relates to a method for predicting the likelihood that an individual will have a neuropsychiatric disorder by determining the presence of prepro BDNF or fragment thereof containing the reference or variant amino acid at position −63. The method comprises obtaining a sample from an individual to be assessed, wherein the sample comprises prepro BDNF protein or fragment thereof, wherein said fragment includes amino acid −63 of prepro BDNF protein. The amino acid present at amino acid −63 of said prepro BDNF is determined, wherein the presence of an methionine at position −63 indicates that the individual has a lower likelihood of developing a neuropsychiatric disorder than an individual having a valine at that position. In one embodiment, the amino acid present at amino acid −63 is determined by contacting the sample with an antibody specific for prepro BDNF or fragment thereof containing the reference amino acid. In another embodiment, the amino acid present at amino acid −63 is determined by contacting the sample with an antibody specific for prepro BDNF or fragment thereof containing the variant amino acid.
In another embodiment, the invention is drawn to a method of predicting the likelihood that an individual will have reduced symptomology associated with a neuropsychiatric disorder, comprising determining the presence of prepro BDNF or fragment thereof containing the reference or variant amino acid as described above. The presence of an methionine at position −63 indicates that the individual has a greater likelihood of having reduced symptomology associated with a neuropsychiatric disorder than an individual having a valine at that position.
The invention is also drawn to kits for us
DePaulo J. Raymond
Lander Eric S.
McInnis Melvin G.
Sklar Pamela
Hamilton Brook Smith & Reynolds P.C.
Holbrook Pamela
Kunz Gary L.
Whitehead Institute for Biomedical Research
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