Nucleic acids encoding type I interferon variants

Details Nucleic acids encoding type I interferon variants Nucleic acids encoding type I interferon variants

1992-09-11

1995-01-03

Draper, Garnette D.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

530351, 435 6951, 4353201, 935 10, C07H 2104

Patent

active

053788230

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention relates to new variants derived from type I interferons, obtained from yeast by recombinant DNA techniques.
Interferons were originally identified by their capacity for preventing viral replication. They constitute a family of proteins which have been divided into different groups. The classification currently proposed for interferons distinguishes two main types: trophoblastins; interferons were previously known under the respective names .alpha.-I interferon (class I .alpha.) and .alpha.-II interferon (class II .alpha.), and trophoblastins could have been classified among the .alpha.-III interferons.
Apart from their antiviral activity, interferons can possess other functions. For example, it has already been established that, in some mammals such as cattle and sheep, trophoblastin participates in the phenomenon of maternal recognition of gestation.
Ovine trophoblastin or oTP has been demonstrated, respectively, by MARTAL et al. [J. Reprod. Fert., 56, 63-73 (1979); Pro. 10th intern. Congress on Anim. Reprod. and A.1., Urbana-Champaign (USA), 11, 509 (short communication) 1984)] and GODKIN et al. [J. Reprod. Fert., 65, 141-150 (1982)] in sheep, where it is produced in abundance by the embryo between the 12th and the 21st day of gestation; in cattle, it is produced between the 16th and the 24th day. It exists in at least 5 isoforms corresponding to different alleles. These isofoms are described in the international PCT application published under No. WO 89/08,706 in the name of the INSTITUT NATIONAL DE LA RECHERCHE AGRONOMIQUE. The molecular weight of trophoblastin is 20 kDa and its isoelectric point is between 5.3 and 5.5, depending on the isoform in question. Trophoblastins have been best characterized in certain ruminants. However, recent studies show that trophoblastin-like molecules also appear to exist in other mammals (horse, rabbit) and in man.
The trophoblastin produced by embryos possesses like the other interferons, miscellaneous biological activities.
Trophoblastin participates, in particular, in the mechanism of recognition of the embryo by the maternal body.
In most cases, the length of a gestation period greatly exceeds that of the luteal phase of the ovarian cycle. When fertilization has taken place, certain mechanisms occur in order to prolong the life of the corpus luteum and to prevent a return of the ovarian cycle. In ruminants, the embryo emits a biochemical signal in the form of trophoblastin (oTP). This substance enables the body to continue to secrete progesterone, a hormone which is essential eryonic for normal embryonic development.
GODKIN et al. [J. Reprod. Fert., 71, 57-64 (1984)] have shown that the intrauterine injection of purified oTP prolongs the secretion of luteal progesterone for a few days in recipient cycling ewes. FINCHER et al. [J. Reprod. Fert., 76, 425-433 (1986)] have found that the injection of natural oTP into the uterus delays oxytocin- or estradiol-induced luteolysis by several days and is accompanied by a reduction in prostaglandin F.sub.2.alpha. secretion. Similar observations have been made with recombinant class I .alpha. interferons [PLANTE et al., Endocrinology 122, 2342-2344, (1988); STEWART et al., (1989) J. Repr. Fert. Supp. p. 127-138].
Trophoblastin is secreted by the embryo only during a relatively short period: from the 16th to the 24th day of gestation as regards cattle and from the 12th to the 22nd day of gestation in the case of sheep.
If the mother and the embryo are asynchronous, that is to say if the embryo secretes trophoblastin before the mother is physiologically capable of being sensitive thereto and of responding to such a stimulation, the corpus luteum regresses and the embryo dies. This possibility is especially critical when embryo transfer is being undertaken. To date, the failure rate in embryo transfer is greater than 30%. This is especially disastrous from an economic standpoint, the situation being still more marked in the case of in vitro fertilization.
A large number of embryo

REFERENCES:
patent: 4782139 (1988-11-01), DiMarchi et al.
E. Degryse et al. Gene 118:47-53 1992.
I. Palva et al., "Secretion of Interferon by Bacillus subtilis", Gene, vol. 22, 1983, pp. 229-235.
K. M. Zsebo et al., "Protein Secretion from Saccharomyces cerevisiae Direction by the Prepro-.alpha.-factor Leader Region", The Journal of Biological Chemistry, vol. 261, No. 12, May 5, 1986, pp. 5858-5865.

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