Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-10-01
2002-04-09
Nolan, Patrick J. (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200
Reexamination Certificate
active
06368797
ABSTRACT:
BACKGROUND OF THE INVENTION
In general, the invention relates to methods for treating a neurological disease.
Neurological diseases, for example, Alzheimer's disease, are often difficult to diagnose and occur in the population in a manner which is difficult to predict. A method that would allow one to identify subjects having a neurological disease, or being at risk for developing a neurological disease, would allow for the more timely administration of an appropriate therapy.
The GPIIIa gene encodes a 788 amino acid polypeptide with a 26-residue signal peptide, a 29-residue transmembrane domain near the carboxy terminus, and four cysteine-rich domains of 33-38 residues each (Zimrin et al.,
J Clin. Invest.
81:1470-1475 (1988)). Two different antigenic forms of GPIIIa, alloantigens PlA1 and PlA2 (for Platelet Antigen 1 and 2), have been described and can be distinguished using a monoclonal antibody (Weiss et al.,
Tissue Antigens
46:374-381 (1995)). The most predominant form of GPIIIa, PlA1, is carried by 98% of the Caucasian population. The rarer form of GPIIIa, PlA2, has sustained a point mutation at base 192 that causes a nucleotide change from a T to a C and thus a leucine to proline (CTG>CCG) amino acid substitution at residue position 33 (Newman et al.,
J. Clin. Invest.
83:1778-1781 (1989)).
The GPIIb polypeptide is the larger component of the GPIIIa/GPIIb complex and comprises two disulfide-linked subunits of 137 amino acids and 871 amino acids each. The larger GPIIb polypeptide has a 26 amino acid signal sequence, a potential transmembrane domain, and four stretches of 12 amino acids each that are homologous to the calcium binding sites of calmodulin and troponin C (Poncz et al.,
J Biol. Chem.
262(18):8476-8482 (1987)). Mutational analysis of these domains has indicated that these calcium-binding domains are required for the correct folding and transport of the GPIIb polypeptide to the cell surface (Basani et al.,
Blood
88:167-173 (1996)). Two antigenic forms of GPIIb, Bak
a
and Bak
b
, have been described and can be distinguished using specific antisera. The less common form of GPIIb (i.e., Bak
b
) was determined to have a T to G point mutation that results in an isoleucine to serine substitution at amino acid position 843 (Lyman et al.,
Blood
75:2343-2348 (1990)).
SUMMARY OF THE INVENTION
The present invention provides methods for identifying or treating a subject at risk for, or diagnosed with, a neurological disease.
In the first aspect, the invention provides a method for identifying a subject at risk for a neurological disease by: identifying the subject; determining the genotype or phenotype of the GPIIIa or GPIIb locus of the subject; and determining the presence of a variant GPIIIa or a variant GPIIb allele or isoform, where the presence of the variant GPIIIa allele or isoform or the variant GPIIb allele or isoform is indicative of the subject having an increased risk of the neurological disease. Preferably, the neurological disease is Alzheimer's Disease (AD).
In the second aspect, the invention provides a method for diagnosing a subject with a neurological disease by: identifying the subject; determining the genotype or phenotype of the GPIIIa or GPIIb locus of the subject; and determining the presence of a variant GPIIIa or a variant GPIIb allele or isoform, where the presence of the variant GPIIIa allele or isoform or the variant GPIIb allele or isoform is indicative of the subject having a likelihood of the neurological disease.
In the third aspect, the invention provides a method for characterizing the genotype of at least one subject involved in a clinical trial of a therapy for the treatment of a neurological disease by: identifying the subject; determining the genotype or phenotype of the GPIIIa or GPIIb locus of the subject before, during, or after the clinical trial; and determining the presence of a variant GPIIIa or a variant GPIIb allele or isoform, where the presence of the variant GPIIIa allele or isoform or the variant GPIIb allele or isoform places the subject into a subgroup for the clinical trial. Preferably, the genotype or phenotype is indexed against the efficacy or side-effects of the therapy.
In the fourth aspect, the invention provides a method for treating a subject with a neurological disease by: identifying the subject; determining the genotype or phenotype of the GPIIIa or GPIIb locus of the subject; determining the presence of a variant GPIIIa or a variant GPIIb allele or isoform; and determining the preferred therapy for the treatment of the neurological disease.
In the fifth aspect, the invention provides a method for treating a subject at risk for a neurological disease by: identifying the subject; determining the genotype or phenotype of the GPIIIa or GPIIb locus of the subject; determining the presence of a variant GPIIIa or a variant GPIIb allele or isoform; determining the GPIIIa or GPIIb allele status of the subject, where the allele status is predictive of patient outcome or drug efficacy.
In a preferred embodiment of the above aspects, the method includes determining the presence of both the variant GPIIIa allele or isoform and the variant GPIIb allele or isoform.
In other preferred embodiments of the above aspects, the neurological disease may be Alzheimer's disease (AD), a non-AD neurological disease, or a neurological disease selected from the group consisting of Alzheimer's disease, neurofibromatosis, Huntington's disease, depression, amyotrophic lateral sclerosis, multiple sclerosis, stroke, Parkinson's disease, and multi-infarct dementia.
In other preferred embodiments of the above aspects, the determining may be performed using a nucleic acid that specifically binds a nucleic acid encoded by the variant GPIIIa allele or the variant GPIIb allele. In other preferred embodiments of the above aspects, the determining may be performed using an antibody that specifically binds a polypeptide encoded by the variant GPIIIa allele or the variant GPIIb allele, but does not bind a polypeptide encoded by a wild-type GPIIIa allele or a wild-type GPIIb allele.
In other preferred embodiments of the above aspects, the variant GPIIIa allele may have a point mutation at nucleotide base 192 of SEQ ID NO: 2 or encode a polypeptide with a proline at amino acid position 33 of SEQ ID NO: 4. In other preferred embodiments of the above aspects, the variant GPIIb allele may have a point mutation at nucleotide base 2622 of SEQ ID NO: 6 or encode a polypeptide with a serine at amino acid position 843 of SEQ ID NO: 8.
The presence of a variant allele may be determined by genotyping nucleic acids from the subject or by assaying for the presence of a protein having alterations encoded by the variant nucleic acid.
By “neurological disease” is meant a disease, which involves the neuronal cells of the nervous system. Specifically included are: prion diseases (e.g, Creutzfeldt-Jakob disease); pathologies of the developing brain (e.g., congenital defects in amino acid metabolism, such as argininosuccinicaciduria, cystathioninuria, histidinemia, homocystinuria, hyperammonemia, phenylketonuria, tyrosinemia, and fragile X syndrome); pathologies of the mature brain (e.g., neurofibromatosis, Huntington's disease, depression, amyotrophic lateral sclerosis, multiple sclerosis); conditions that strike in adulthood (e.g. Alzheimer's disease, Creutzfeldt-Jakob disease, Lewy body disease, Parkinson's disease, Pick's disease); and other pathologies of the brain (e.g., brain mishaps, brain injury, coma, infections by various agents, dietary deficiencies, stroke, multiple infarct dementia, and cardiovascular accidents).
By “cognitive enhancers” is meant drugs which enhance a) memory performance, whether it is verbal memory, spatial memory, or factual memory and b) learning capacity.
By “cholinomimetic therapy” is meant any drug that mimics the function of acetylcholine or enhances the activity of acetylcholine synthesizing cells. These drugs include, but are not limited to, inhibitors of acetylcholi
Bieker-Brady Kristina
Clark & Elbing LLP
Nolan Patrick J.
Variagenics Inc.
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