Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-07-12
2004-10-05
Horlick, Kenneth R. (Department: 1637)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S007100
Reexamination Certificate
active
06800440
ABSTRACT:
The invention disclosed herein was made with Government support under NIH Grant No. HL60056-02 from the National Heart, Lung and Blood Institute. Accordingly, the government has certain rights in this invention.
Throughout this application, various publications are referenced within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citations for these references may be found immediately preceding the claims.
BACKGROUND OF THE INVENTION
Familial Primary Pulmonary Hypertension (PPH, MIM 178600) is a rare (1 in 10
5
to 10
6
) autosomal dominant disorder with reduced penetrance that has been mapped to a 3-centimorgan region on chromosome 2q34 (PPH1 locus) (Morse et al. 1996; Morse et al. 1997; Nichols et al. 1997; Deng et al. 2000). It is characterized by monoclonal plexiform lesions of proliferating endothelial cells in pulmonary arterioles (Lee et al. 1998) that lead to elevated pulmonary artery pressures, right ventricular failure, and death (Rich et al. 1987). The disease can occur from infancy throughout life with a mean age of onset of 36 years and has a 2:1 ratio of affected females to males. Without intervention, the median survival is less than three years after diagnosis (D'Alonzo et al. 1991), although recent advances, such as long-term prostacyclin therapy (Barst et al. 1996) and transplantation (Pasque et al. 1995) have significantly improved the quality of life and survival in some patients. Although FPPH is rare, cases secondary to known etiologies are more common and include those associated with the appetite suppressant drugs, including phentermine-fenfluramine (Douglas et al. 1981; Abenhaim et al. 1996).
SUMMARY OF THE INVENTION
This invention provides a method of detecting whether a subject is either predisposed to or afflicted with a pulmonary disease which comprises (1) obtaining a suitable sample from the subject; (2) detecting in the sample a bone morphogenetic protein receptor-II mutation which is not present in wildtype bone morphogenetic protein receptor-II, wherein the presence of a mutation indicates that the subject is predisposed to or afflicted with the pulmonary disease.
This invention provides a method of detecting whether a subject is either predisposed to or afflicted with a pulmonary disease which comprises:
a) obtaining a suitable nucleic acid sample from the subject; and
b) detecting in the nucleic acid the presence of a mutation in a gene which encodes bone morphogenetic protein receptor-II,
wherein the presence of a mutation indicates that the subject is predisposed to or afflicted with the pulmonary disease.
In one embodiment of the subject invention, the pulmonary disease is Primary Pulmonary Hypertension. In one embodiment of the subject invention, the Primary Pulmonary Hypertension is Familial Primary Pulmonary Hypertension.
This invention provides a method of predicting an increased likelihood of a subject's giving birth to twins or triplets which comprises:
a) obtaining a suitable nucleic acid sample from the subject;
b) detecting the presence of one copy of a mutant gene which encodes bone morphogenetic protein receptor-II, thereby indicating that the subject is heterozygous for the mutation,
wherein heterozygosity predicts an increased likelihood of the subject giving birth to twins or triplets.
This invention provides a method of predicting an increased likelihood of a subject having a miscarriage prior to giving birth to a child which comprises:
a) obtaining a suitable nucleic acid sample from the subject;
b) detecting the presence of two copies of a mutant gene which encodes bone morphogenetic protein receptor-II, thereby indicating that the subject is homozygous for the mutation,
wherein homozygosity predicts an increased likelihood of the subject having a miscarriage prior to giving birth to a child.
This invention provides a method of preventing and/or treating Familial Primary Pulmonary Hypertension in a subject which comprises introducing a nucleic acid comprising a gene encoding wildtype bone morphogenetic protein receptor-II protein into a suitable cell under conditions such that the nucleic acid expresses the wildtype bone morphogenetic protein receptor-II protein so as to thereby prevent and/or treat Familial Primary Pulmonary Hypertension in the subject.
This invention provides a method of preventing and/or treating Familial Primary Pulmonary Hypertension in a subject which comprises administering to the subject an amount of wildtype bone morphogenetic protein receptor-II effective to prevent and/or treat Familial Primary Pulmonary Hypertension so as to thereby prevent and/or treat Familial Primary Pulmonary Hypertension in the subject.
This invention provides a method of detecting whether a subject is either predisposed to or afflicted with Familial Primary Pulmonary Hypertension which comprises:
a) obtaining a suitable nucleic acid sample from the subject; and
b) detecting the presence of a (GGC)
12
trinucleotide repeat at the 5′ end of the bone morphogenetic protein receptor-II gene at positions 928 to 963,
wherein the presence of the trinucleotide repeat indicates that the subject is either predisposed to or afflicted with Familial Primary Pulmonary Hypertension.
This invention provides a method of screening for a compound capable of treating Familial Primary Pulmonary Hypertension which comprises:
a) contacting a cell which expresses a mutant bone morphogenetic protein receptor-II with the compound; and
b) determining whether the compound is capable of reversing the functional deficit in Familial Primary Pulmonary Hypertension,
wherein a reversal of the functional deficit indicates that the compound is capable of treating Familial Primary Pulmonary Hypertension.
This invention provides a method of obtaining a composition which comprises:
a) identifying a compound capable of treating Familial Primary Pulmonary Hypertension by the above method; and
b) admixing the compound so identified or a homolog or derivative thereof with a carrier.
This invention provides a transgenic animal which comprises a mutation in a gene which encodes a bone morphogenetic protein receptor-II.
REFERENCES:
patent: 6291206 (2001-09-01), Wozney et al.
patent: 6306622 (2001-10-01), Rosenbaum et al.
patent: 6642002 (2003-11-01), Loyd et al.
patent: 2002/0102576 (2002-08-01), Loyd et al.
patent: 02/06534 (2002-01-01), None
Knowles James A.
Morse Jane H.
Cooper & Dunham LLP
Horlick Kenneth R.
The Trustees of Columbia University in the City of New York
White John P.
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