Chemistry: molecular biology and microbiology – Spore forming or isolating process
Patent
1992-04-16
1994-11-22
Weimar, Elizabeth C.
Chemistry: molecular biology and microbiology
Spore forming or isolating process
4352401, 4352402, 4352403, 43524031, 435806, 600 33, 600 34, 800DIG4, 800DIG6, 800 2, A61B 1742, A61D 700, C12N 506
Patent
active
053668880
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of Leukemia Inhibitory Factor (LIF) in the enhancement of development and maintenance of animal or mammalian embryos and the use of same to enhance impregnation.
LIF is a protein that has previously been cloned, produced and purified in large quantities in recombinant form from both E. coli and yeast cells (International patent application Ser. No. PCT/AU88/00093). LIF has been defined as a factor, the properties of which include: such as M1 cells, with associated differentiation of the leukaemic cells; and murine LIF or human LIF (defined in International patent application Ser. No. PCT/AU88/00093) for binding to specific cellular receptors on M1 cells or murine or human macrophages.
A major difficulty associated with present in vitro fertilisation (IVF) and embryo transfer (ET) programs, particularly in humans, is the tow success rate "achieved" on implantation of fertilised embryos. Currently, in human IVF programs, the implantation rate may be as low as 10%, leading to the present practice of using up to four fertilised embryos in each treatment which, in turn, leads occasionally to multiple births. Accordingly, there is a need to improve the implantation rate in human IVF programs. Similarly, in IVF and ET treatments in domestic animals such as sheep, cattle, pigs and goats, it is highly desirable for economic reasons to have as high an implantation rate as possible so as to reduce the numbers of fertilised embryos lost and unsuccessful treatment procedures performed. Furthermore, as with human IVF procedures, the practice of transferring more than one embryo to the recipient animal to ensure pregnancy can result in unwanted multiple births.
One major constraint with embryo transfer is the need to hold embryos in culture media for either relatively short periods of time, perhaps only a few hours prior to transfer or for longer periods of some days, after micromanipulation.
In the development of a mammalian embryo, the fertilised egg passes through a number of stages including the morula and the blastocyst stages. In the blastocyst stage, the cells form an outer cell layer known as the trophectoderm (which is the precursor of the placenta) as well as an inner cell mass (from which the whole of the embryo proper is derived). The blastocyst is surrounded by the zona pellucida, which is subsequently lost when the blastocyst "hatches". The cells of the trophectoderm are then able to come into close contact with the wall of the uterus in the implantation stage. Prior to formation of the embryo proper by the inner cell mass by gastrulation, the whole cell mass may be referred to as "pre-embryo".
Embryo mortality has been attributed to incomplete hatching of the blastocyst from the zona pellucida and/or unsuccessful implantation of the embryo to the uterine wall, possibly due to spontaneous differentiation of the embryonic stem cells (ES) during their period in culture prior to transplantation.
In accordance with the present invention, it has been found that when LIF is included in an in vitro embryo culture medium, the hatching process is enhanced leading to an increased number of embryos completing the development stage by undergoing developmental changes associated with implantation. Thus, LIF is an embryo protective agent. As a result, the implantation rates for IVF and ET programs can be, and are, significantly improved by the use of LIF in the in vitro embryo culture medium.
Furthermore, media containing LIF is suitable for use in early manipulative procedures on the oocyte/embryo such as in vitro fertilisation, embryo splitting and nuclear transfer where survival rates of embryos are low. LIF also has important applications in the growth of totipotent stem cell lines for cloning for inclusion into the media used for the transport of cooled or frozen embryos/semen.
Unless otherwise specified, use of "LIP" herein refers to synthetic recombinant or naturally occurring human, murine and/or livestock or ruminant LIF, such as from sheep, pigs, cows, goats, donkeys and
REFERENCES:
patent: 5166065 (1992-11-01), Williams et al.
Pease, et al. (1990) "Isolation of Embryonic Stem (ES) Cells in Media Supplemented with Recombinant Leukemia Inhibitory Factor (LIF)", Developmental Biology 141, 344-353.
Williams, et al. 1988 "Myeloid Leukemia Inhibitory Factor Maintains the Developmental Potential of Embryonic Stem Cells", Nature 336, 684-687.
Soukhanov et al., (eds) 1984, in Webster's II: New Riverside University Dictionary, Houghton Mifflin Co., Boston pp. 699 and 1024.
Pease et al., 1990 Experimental Cell Research, 190:209-211.
Smith et al. 1988. Nature 336:688-690.
Heath et al. 1988 J. Cell Sci. Suppl. 10:259-266.
Hilton et al. 1988 Analytical Biochemistry 173:359-367.
Fry Richard C.
Parr Ronald A.
Amrad Corporation Limited
Stanton Brian R.
Weimar Elizabeth C.
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