Detection of pancreatitis-associated protein for screening for c

Details Detection of pancreatitis-associated protein for screening for c Detection of pancreatitis-associated protein for screening for c

1995-08-30

1998-11-10

Spiegel, Carol A.

Chemistry: molecular biology and microbiology

Maintaining blood or sperm in a physiologically active state...

435 71, 435975, 435331, 435333, 435337, 436518, 436536, 436548, 436811, 5303881, 53038825, 5303891, 5303893, G01N 3353

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058342141

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The human pancreatitis-associated protein (PAP) was isolated, purified and characterized in man and described in the PCT patent application published on 31 Oct. 1991 under the No 91/16428. In the earlier application the PAP was suggested as a means for the detection of a specific disease, acute pancreatitis.
Mucoviscidosis, also called "cystic fibrosis" in English is a very frequent genetic disease in certain populations, which is characterized by a global insufficiency of exocrine secretions of the pancreas and the lung and the exocrine glands in general. Clinically, the disease is associated with abnormally viscous secretions, the mucus formed being capable of obstructing the bronchi and causing serious or mortal disorders.
The mucoviscidosis gene has been localized on human chromosome 7. This gene, called the CFTR gene ("cystic fibrosis transmembrane conductance regulator") shows mutations in different regions in the subjects suffering from mucoviscidosis. Mutations of the same type may be detected on only one of the two chromosomes 7 in subjects called "carriers" but not showing clinical signs of the disease. These persons are heterozygous for the mutation in the CFTR gene.
In the case of a heterozygous mutation, the carrier subject may however suffer certain disorders characteristic of an impairment of the secretory glands. The carrier subject may for example suffer from disorders of the pancreas.
The diagnosis of mucoviscidosis was conducted in the first instance by a test called the "sweat test" which consists of determining the chloride and sodium ions in the sweat of subjects, in particular of children, likely to suffer from this disease. It was possible to correlate the indication of a chloride ion level situated between 60 and 180 mEq/l with the disease in as much as this level is about 40 mEq/l in the normal infant.
Several other types of tests have been successively suggested (Berry, H. K. et al., Am. J. Dis. Child. 1980 134: 930; Crossley, J. R. et al., Lancet 1977 ii: 1093; Forrest, D. C. et al. Arch. Dis. Child. 1981 56 156; Green, M. N. et al., Pediatrics 1968 41: 989; Robinson, P. G. et al., Arch. Dis. Child 1976 51: 301; Schwachman, H. et al., Pediatrics 1949 4: 222), but only the serum determination of trypsin in the newborn (Farriaux J. P. et al., Immunoanal. Biol. Spec. 1992 33: 71) has shown sufficient relevance to still be in force in some countries (Farrell, P. M. et al., Ped. Pulmonol. 1991 supplement 7: 11). This radioimmunological determination is performed on bloodstains deposited on cardboard, the blood being taken from newborn infants for the purposes of screening for other genetic diseases at present screened systematically, phenylketonuria and hypothyroidism. The screening by serum trypsin nonetheless remains very imperfect since the results of a large scale French evaluation program have recently led the French Screening Association not to make it compulsory (Farriaux, J. P. et al. Immunoanal. Biol. Spec. 1992 33: 71).
The principal problem posed by the determination of trypsin in serum is that of false positives (about 1% of the population whereas the incidence of the disease in France is about 0.03% (Farriaux, J. P. et al. Immunoanal. Biol. Spec. 1992 33: 71).


SUMMARY OF THE INVENTION

The inventors have at present demonstrated that the genetic anomalies likely to give rise to disorders characteristic of mucoviscidosis may be reliably correlated in man with an abnormal expression of the PAP from birth.
The object of the present application is the detection of mucoviscidosis or of a mutation in the gene responsible for mucoviscidosis associated with a pancreatic disease by means of a determination of the PAP (pancreatitis-associated protein).
The invention suggests novel agents for carrying out a test for the detection of mucoviscidosis or of a disease of certain exocrine glands, of the pancreas in particular, a disease linked to the existence of a heterozygous mutation in the CFTR gene.
The agents of the invention make it possible to signif

REFERENCES:
patent: 4281061 (1981-07-01), Zuke et al.
patent: 4322274 (1982-03-01), Wilson et al.
patent: 5436169 (1995-07-01), Iovanna et al.
Iovanna et al., "Pancreatitis-Associated Protein a Promising Candidate for Neonatal Screening of CF," Abstracts, Pediatric Pulmonology, Supplement 9, p. 239, No. 138, Sep. 1993.
Itoh et al, "Cloning and Tissue Specific Expression of CDNAs for the Human and Mouse Homologues of Rat Pancreatitis-Associated Protein (PAP)," Biochim. Biophys. 1172: 184-186, 20 Feb. 1993.
Keim et al., "Fragments of PAP . . . in Serum and Urine of Patients With Acute Pancreatitis," Pancreas 7(6): 744, Nov. 1992.
Keim et al., "Human Pancreas-Associated Protein," J. Clin. Invest. 90(6): 2284-2291, 17 Dec. 1992.
Sahel et al., "Pancreatitis-Associated Protein (PAP-H) Serum Levels After ERCP," Gastroenterology 102(4 Suppl 2): A289, Apr. 1992.
Wood, Southern Medical Journal, vol. 72, No. 2, pp. 189-202 (Feb. 1979).
Keim et al, Gastroenterology, vol. 103, pp. 248-254 (1992).
Farrell et al, Pediatric Pulmonology Supplement, vol. 7, pp. 11-18 (1991).

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