Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-04-15
2001-11-06
Clark, Deborah J. R. (Department: 1633)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S004000, C435S007100, C536S023100
Reexamination Certificate
active
06312898
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods for diagnosing a person's susceptibility for having an increased risk for the development of atherosclerosis and a diabetic person's susceptibility for having an increased risk for the development of diabetic retinopathy. The invention relates further to methods for treating persons diagnosed for having increased risk for the development of said diseases, in order to prevent the development of said diseases. The invention also concerns method to investigate or screen pharmaceuticals or genetic aims useful in the treatment of said diseases, by using an animal model including a transgenic animal.
BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Neuropeptide Y (NPY) is a member of the pancreatic polypeptide family and neuromodulator that is secreted widely by neurons of the central and peripheral nervous systems and it is the most abundant peptide in the brain and in the heart (
1
-
4
). NPY is the most potent orexigenic neuropeptide and may have tonic inhibitory action on leptin mediated satiety signal (
2
-
3
,
5
). NPY stimulates insulin secretion (
6
) and insulin-induced glucose uptake in normal rate (
7
). In contrast, insulin and insulin-like growth factor II suppress hypothalamic NPY release (
8
). In animal models of obesity and Type 2 diabetes, enhanced activity of NPY neurons due to hypothalamic resistance of insulin inhibition may contribute to hyperphagia, reduced energy expenditure and obesity (
9
). Further, NPY participates in the control on hypothalamic-pituitary-adrenal axis (
10
). In the cardiovascular system NPY is a vasoconstrictor, it inhibits the release of norepinephrine and potentiates the norepinephrine response (
11
). Interestingly, in experimental diabetes cardiorespiratory responses to NPY have been shown to be altered (
12
-
13
). Further, NPY may have angiogenic properties (
4
) that could enhance the development of atherosclerosis. The widespread effects of NPY are mediated by several different subtypes of NPY receptors (
14
). We identified a rather common leucine7 to proline7 polymorphism (Leu7/Pro) very recently (
15
). This polymorphism was found to be associated with significantly higher serum total- and LDL cholesterol levels particularly in obese subjects in two independent Finnish and one Dutch study population. Further, apolipoprotein B levels were elevated in non-diabetic subjects with Leu7/Pro-polymorphism in one of these populations (
15
). Although the biochemical and physiological link between cholesterol metabolism and NPY is currently not known, the Leu7/Pro-polymorphism of NPY gene should be considered as a new genetic marker for high cholesterol levels in obese subjects.
SUMMARY OF THE INVENTION
According to one aspect, this invention concerns a method for diagnosing a person's susceptibility for having an increased risk for the development of atherosclerosis, said method comprising determining whether said subject has a polymorphism in the signal peptide part of the human preproNPY, said polymorphism comprising the substitution of the position 7 leucine for proline in the signal peptide part of said preproNPY, said polymorphism being indicative of an increased risk for the development of atherosclerosis.
According to another aspect, the invention concerns a method for diagnosing a diabetic person's susceptibility for having an increased risk for the development of diabetic retinopathy, said method comprising determining whether said subject has a polymorphism in the signal peptide part of the human preproNPY, said polymorphism comprising the substitution of the position 7 leucine for proline in the signal peptide part of said preproNPY, said polymorphism being indicative fo an increased risk for the development of diabetic retinopathy.
According to a third aspect, the invention concerns a method for treating a person, diagnosed for having an increased risk for the development of diabetic retinopathy, for the prevention of developing any of said diseases, comprising administering to said person an effective amount of an agent counteracting the influence of the mutated NPY gene.
According to a fourth aspect, the invention concerns a method for treating a person, diagnosed for having an increased risk for the development of atherosclerosis, or for treating a diabetic person, diagnosed for having an increased risk for the development of diabetic retinopathy, for the prevention of developing any of said diseases, comprising subjecting the person to specific gene therapy aimed to repair the mutated NPY signal peptide sequence.
According to a fifth aspect, the invention concerns a method to investigate or screen pharmaceuticals or genetic aims useful in the treatment of atherosclerosis or diabetics retinopathy, by using an animal model including a transgenic animal which carries a human DNA sequence comprising a nucleotide sequence encoding a prepro-neuropeptide Y (preproNPY) or part thereof encoding mature human NPY peptide, where the leucine amino acid in position 7 of the signal peptide part of said preproNPY i) is unchanged or ii) has been replaced by proline.
According to a sixth aspect, the invention concerns a method to investigate or screen pharmaceuticals or genetic aims useful in the treatment of atherosclerosis or diabetic retinopathy, by using an animal model including a transgenic animal, which carries a DNA sequence comprising a nucleotide sequence encoding otherwise normal mouse NPY sequence or part thereof encoding mature mouse NPY peptide, but in which the nucleotide sequence encoding the mouse signal peptide is replaced by human signal peptide sequence encoding either normal or mutated human signal peptide.
REFERENCES:
patent: 5455164 (1995-10-01), Turner
patent: 9527782 (1995-10-01), None
patent: 9850563 (1998-11-01), None
Chew, E.Y. et al. (1996) “Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy.”Arch. Ophthalmol.114:1079-1084.
Ito, H. et al. (1996). “Risk factor analysis for macrofasclar complication in nonobese NIDDM patients: multiclinical study for diabetic macroangiopathy (MSDM).”Diabetes45 Suppl. 3:S19-S23.
Ueda, H. et al. (1993). “Importance of serum cholesterol level in development of diabetic autonomic neuropathy.”Diabetes Res. Clin. Practice21:123-126.
Uusitupa, M.I.J. et al. (1998). “Neuropeptide Y: a novel link between the neuroendocrine system and cholesterol metabolism.”Ann. Med.30:508-510.
Karvonen, M.K. et al. (1998). “Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels.”Nature Medicine4:1434-1437.
Roche, C. et al. (1997). “Genetic studies of neuropeptide Y and neuropeptide Y receptors Y1 and Y5 regions in morbid obesity.”Diabetologia40:671-675.
Thorsell, A. et al. (1996). “Cationic lipid-mediated delivery and expression of prepro-neuropeptide Y cDNA after intraventricular administration in rat: feasibility and limitations.”Regulatory Peptides61:205-211.
Nystrom, F. et al. (1996). “A Population Study of Plasma Neuropeptide Y: Correlations with Components of the Metabolic Syndrome.”Blood Pressure5:349-353.
Minth, C.D. et al. (1984). “Cloning, characterization, and DNA sequence of a human cDNA encoding neuropeptide tyrosine.”Proc. Natl. Acad. Sci. USA81:4577-4581.
Larhammar, D. et al. (1987). “Structure and expression of the rat neuropeptide Y gene.”Proc. Natl. Acad. Sci. USA84:2068-2072.
Erickson, J.C. et al. (1996). “Attenuation of the obesity syndrome of ob/ob mice by the loss of neruopeptide Y.”Science274:1704-1707.
Jaenisch, R. (1988). “Transgenic Animals.”Science240:1468-1474.
Karvonen Matti
Koulu Markku
Pesonen Ullamari
Uusitupa Matti
Clark Deborah J. R.
Hormos Medical Oy Ltd.
Rothwell Figg Ernst & Manbeck p.c.
Sorbello Eleanor
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