Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-07-14
2003-06-03
Jones, W. Gary (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S023100
Reexamination Certificate
active
06573049
ABSTRACT:
FIELD OF THE INVENTION
In general, the present invention relates to methods for diagnosing or treating a disease, as well as for identifying a subject for participation in a clinical trial, and identifying a subject at risk for a disease.
BACKGROUND OF THE INVENTION
Many diseases are difficult to diagnose because the appropriate diagnostic tools have not yet been identified. The ability to predict that an a symptomatic subject is at risk for developing a disease is even more difficult. A method that would provide a better means by which a disease could be diagnosed, or the risk of developing a disease could be assessed, would be beneficial. The result of having better diagnostic or risk assessment tools would be the more timely administration of appropriate therapies. In addition, not all patients with the same disease respond with equal efficacy to the same therapy. The genotype of a patient may affect the pharmacological efficiency among patients having the same disease. If the genotype of a diseased patient is known, optimal therapies can be determined and administered for the patient, resulting in a faster recovery from the disease.
SUMMARY OF THE INVENTION
The present invention provides methods for diagnosing or treating a disease, as well as for identifying a subject for participation in a clinical trial, and for identifying a subject at risk for a disease. The methods of the invention involve genotyping or phenotyping subjects for the presence of a variant PON1 allele. The information obtained from the determination of the PON1 allele status can be used to diagnose the subject as having a disease, or to identify the subject as being at risk for a disease, or to determine the appropriate therapy for the subject. PON1 allele status determination can also be helpful in designing and assessing the results of a clinical trial aimed at developing a therapy for the treatment of a disease. In a related aspect, the invention features a treatment protocol that provides a prediction of patient outcome.
The human PON1 gene, as reviewed by Mackness et al. (Gen. Pharmac. 31:329-336, 1998), encodes a serum paraoxonase protein. The protein is a 45-kDa glycoprotein that is associated with high density lipoprotein. The protein functions by hydrolyzing organophosphate insecticides and nerve gases, and is responsible for determining the selective toxicity of these compounds in mammals.
Historically, the amino acid residues of the paraoxonase protein may be numbered in two different ways. The amino acids of paraoxonase may be numbered with methionine (beginning at base pair 10) or with alanine (beginning at base pair 13; as used herein) as the first amino acid (see
FIG. 1
; SEQ ID NO:1). A variant PON1 allele may occur, for example, at amino acid position 54, as used herein, or 55, depending on which numbering system is used. For this reason, the mutation Met54Leu is equal to the mutation Met55Leu. For clarity, this application utilizes the numbering system beginning with alanine as the first amino acid, and therefore refers to PON1 alleles at amino acid positions 54 and 191.
Accordingly, in one aspect, the present invention features a method for identifying a subject at risk for a disease. The method includes genotyping or phenotyping the PON1 locus of a subject, and determining the presence of a variant PON1 allele or isoform. The presence of such a variant allele or isoform indicates an increased risk for the disease.
In a second aspect, the present invention features a method for diagnosing a subject with a disease. The method includes genotyping or phenotyping the PON1 locus of a subject, and determining the presence of a variant PON1 allele or isoform. The presence of such a variant allele or isoform indicates an increased risk for the disease.
In a third aspect, the present invention features a method for identifying a subject for participation in a clinical trial of a therapy for the treatment of a disease. The method includes genotyping or phenotyping the PON1 locus of a subject, and determining the presence of a variant PON1 allele or isoform, where the presence of a variant PON1 allele or isoform places the subject into a subgroup for a clinical trial of a drug.
In a fourth aspect, the present invention features a method of treating a subject with a disease. The method includes genotyping or phenotyping the PON1 locus of a subject, determining the presence of a variant PON1 allele or isoform, and determining the preferred therapy for the treatment of the disease.
In preferred embodiments of all of the above aspects of the invention, the disease may be a neurological disease. The neurological disease can be Alzheimer's disease (AD), or a non-Alzheimer's disease neurological disease (non-AD). In a preferred embodiment, the neurological disease is Alzheimer's disease, neurofibromatosis, Huntington's disease, depression, amyotrophic lateral sclerosis, multiple sclerosis, stroke, Parkinson's disease, or multi-infarct dementia. In further embodiments of the above aspects of the invention, the variant PON1 allele or isoform contains a deletion, insertion, or missense mutation. In another preferred embodiment, the PON1 allele status is heterozygous or homozygous for the PON1 Met54Leu allele.
In preferred embodiments of the invention, the therapy can be a cholinomimetic therapy (e.g. tacrine) or a non-cholinomimetic therapy (e.g., a vasopressinergic therapy). In another preferred embodiment, the therapy can be probucol, a monoamine oxidase inhibitor, a muscarinic agonist, a neurotrophic factor, a noradrenergic factor, an antioxidant, an anti-inflammatory agent, corticotrophin-releasing hormone (CRH), somatostatin, substance P, neuropeptide Y, and thyrotrophin-releasing hormone (TRH).
In a particular application of the invention, all of the above aspects feature a determination of the PON1 allele status of the subject, where a determination of the PON1 allele status, e.g., of the Met54Leu variant, as being heterozygous or homozygous, is predictive of the patient having a poor response to a therapy for a neurological disease (e.g., Alzheimer's disease).
The invention also provides a method for treating a patient at risk for a disease by a) identifying a patient with a risk, b) determining the PON1 allele status of the patient, and c) converting the data obtained in step b) into a treatment protocol that includes a comparison of the PON1 allele status with the allele frequency of a control population. This comparison allows for a statistical calculation of the patient's risk for having a particular disease. In preferred embodiments, the method provides a treatment protocol that predicts a patient being heterozygous or homozygous for the Met54Leu allele to respond poorly to a cholinomimetic (e.g., tacrine) or specific non-cholinomimetic (e.g., vasopressinergics) therapy for a neurological disease, and a patient who is wild type homozygous, to respond favorably to the therapy.
The invention also provides treating a patient at risk for, or diagnosed with, a disease using the above method, and conducting an additional step c) which involves determining the apolipoprotein E allele (e.g., apoE4) or butyrylcholinesterase allele (e.g., BCHE-K) load status of the patient. This method further involves converting the data obtained in steps b) and c) into a treatment protocol that includes a comparison of the allele status of these steps with the allele frequency of a control population. This affords a statistical calculation of the patient's risk for having a disease, for example, a neurological disease. In a preferred embodiment, the method is useful for treating a neurological disease such as Alzheimer's disease, neurofibromatosis, Huntington's disease, depression, amyotrophic lateral sclerosis, multiple sclerosis, stroke, Parkinson's disease, or multi-infarct dementia. In addition, in related embodiments, the methods provide a treatment protocol that predicts a patient to be at high risk for a neurological disease and responding poorly to a ch
Bieker-Brady Kristina
Clark & Elbing LLP
Goldberg Jeanine
Jones W. Gary
Nuvelo, Inc.
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