Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1997-02-11
1999-09-14
Achutamurthy, Ponnathapura
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 794, 436 63, 436 65, 436 86, 436 87, 436501, 436518, 53038824, 4241391, 4241411, G01N 3353, G01N 33543, C07K 1600
Patent
active
059521821
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the detection of possible genetic abnormalities and more particularly to those of Down's Syndrome.
Prenatal screening for Down's syndrome has become an important and established part of modern antenatal care. At present, most screening programmes depend upon maternal age in combination with the measurement of human chorionic gonadotrophin (hCG) and .alpha. feto-protein (AFP), with or without unconjugated oestriol (uE3), in maternal serum at 16 weeks gestation. Such an approach will detect approximately 65% of Down's affected pregnancies for an amniocentesis rate of 5%. However, it has long been hoped that improvements in screening might increase this detection rate, while minimising the amniocentesis rate, and also allow testing to be performed earlier in pregnancy. To this end, it was recently reported that inhibin, a heterodimeric glycoprotein produced by various tissues, including the placenta, was elevated in the second trimester in maternal serum from Down's syndrome pregnancies compared to normal pregnancies (van Lith et al. 1992. Second-trimester maternal serum immunoreactive inhibin as a marker for fetal Down's syndrome, Prenatal Diagnosis 12, 801-806; and Spencer, K. et al. 1993. Elevated levels of maternal serum inhibin immunoreactivity in second trimester pregnancies affected by Down's syndrome, Annals of Clinical Biochemistry 30, 219-220).
In addition, a number of fetal and placental proteins have undergone initial evaluation of their usefulness as first, rather than second, trimester maternal serum markers for Down's syndrome (Macintosh M. C. M. and Chard, T., 1993, Biochemical screening for Down's syndrome in the first trimester of pregnancy, Fetal and Maternal Medicine Reviews 5, 181-190 and references therein).
Screening earlier in pregnancy, in the first trimester, would have considerable advantages over the current second trimester timing. Several maternal serum markers, including .alpha. fetoprotein (AFP), b-subunit of human chorionic gonadotrophial (.beta.-hCG). Pregnancy-associated placental protein A (PAPP-A) have been assessed as first trimester markers of which .beta.-hCG appears the most promising of these to date. A combination of maternal age, .beta.-hCG and AFP has been predicted to otter a detection rate of 54% for an amniocentesis rate (or false positive rate--FPR) of 5% (Aitken et al, 1993, Biochemical screening for chromosome abnormalities and neutral tube defects in the first trimester, Journal of Medical Genetics 30,336). Clearly, there is still a need for a more reliable test with improved sensitivity and specificity which would preferably be applicable to both the first or second trimester, but especially the former.
It has now been established that enhanced levels of a particular species of the hormone Inhibin in maternal body fluids are indicative of the possible presence of fetal abnormality of this kind.
The hormone Inhibin is known to be involved in human and animal reproduction although its precise role is not yet established. It is now known that there is a "family" of inhibins known as Inhibin A and Inhibin B. These molecules are dimers composed of two sub-unit monomers. Inhibin-A consists of two protein sub-units, termed .alpha. and .beta.A, which are joined together by disulphide bonds.
European patent 185,034, dating from applications in 1984 and 1985, precedes the discovery of a family of inhibins and discloses one dimeric form of inhibin, which it identifies in terms of molecular weight, sub-unit structure, and other properties. EP 185,034 sizes one sub-unit at molecular weight 14,000+/-2000 kilodaltons (12K or 14K) and the larger sub-unit as a 44K molecule. Later research suggests that the primary active form of dimeric inhibin-A in biological fluids is of size 32K, corresponding to a 12K .beta.A and a 20K .alpha. sub-unit. The 32K inhibin is the mature form produced by post-translational processing of precursor forms of molecular weight 65K and 56K. Immunoreactive .alpha. monomer also circulates in the body, a factor which complic
REFERENCES:
Groome et al., Hybridoma., vol. 10., Issue. 2., pp. 309-316., 1991.
Groome et al., Journal of Immunological Methods., vol. 165., pp. 167-176., 1993.
J. M. M. Van Lith et al., Prenatal Diagnostics., vol. 12., pp. 801-806., 1992.
Groome Nigel Patrick
Wallace Euan Morrison
Achutamurthy Ponnathapura
Browning Clifford W.
Oxford Brookes University
Ponnaluri P.
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