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WO1991003551A1 - Production d'hormone de croissance dans le lait d'animaux transgeniques - Google Patents

Production d'hormone de croissance dans le lait d'animaux transgeniques Download PDF

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Publication number
WO1991003551A1
WO1991003551A1 PCT/US1990/005130 US9005130W WO9103551A1 WO 1991003551 A1 WO1991003551 A1 WO 1991003551A1 US 9005130 W US9005130 W US 9005130W WO 9103551 A1 WO9103551 A1 WO 9103551A1
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WIPO (PCT)
Prior art keywords
growth hormone
milk
transgenic mammal
mammal
hgh
Prior art date
Application number
PCT/US1990/005130
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English (en)
Inventor
Vermuri B. Reddy
Cha-Mer Wei
Anthony J. Garramone
Original Assignee
Tsi-Mason Research Institute
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Publication date
Application filed by Tsi-Mason Research Institute filed Critical Tsi-Mason Research Institute
Publication of WO1991003551A1 publication Critical patent/WO1991003551A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A01K67/0278—Knock-in vertebrates, e.g. humanised vertebrates
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B41/00—After-treatment of mortars, concrete, artificial stone or ceramics; Treatment of natural stone
    • C04B41/45—Coating or impregnating, e.g. injection in masonry, partial coating of green or fired ceramics, organic coating compositions for adhering together two concrete elements
    • C04B41/50—Coating or impregnating, e.g. injection in masonry, partial coating of green or fired ceramics, organic coating compositions for adhering together two concrete elements with inorganic materials
    • C04B41/5076—Coating or impregnating, e.g. injection in masonry, partial coating of green or fired ceramics, organic coating compositions for adhering together two concrete elements with inorganic materials with masses bonded by inorganic cements
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/61—Growth hormone [GH], i.e. somatotropin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/15—Humanized animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/01—Animal expressing industrially exogenous proteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2830/00—Vector systems having a special element relevant for transcription
    • C12N2830/008—Vector systems having a special element relevant for transcription cell type or tissue specific enhancer/promoter combination
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2830/00—Vector systems having a special element relevant for transcription
    • C12N2830/80—Vector systems having a special element relevant for transcription from vertebrates
    • C12N2830/85—Vector systems having a special element relevant for transcription from vertebrates mammalian

Definitions

  • Human growth hormone is one member of the cascade of hormones responsible for normal growth in vertebrates. The cascade is initiated when, in response to neurological stimulation,
  • GHRF growth hormone releasing factor
  • somatostatin a positive growth factor called growth hormone releasing factor (GHRF)
  • GHRF stimulates the pituitary to release growth hormone (GH), which in turn acts on the liver to produce insulin-like growth factor I. This in turn binds to receptors on the cells of
  • Somatostatin acts on the pituitary to inhibit release of growth horomone.
  • the short children are deficient in endogenous GH, probably as a result of some genetic defect.
  • Administration of exogenous GH is effective in overcoming this deficiency in most of these individuals.
  • children of short stature have normal levels of endogenous GH, and thus are probably somewhat
  • hGH osteoporosis
  • hGH has been available only in limited quantities as a purification product from the pituitaries of human cadavers. Although the recent cloning and the expression of this cloned gene in bacteria has increased availability of hGH, as first reported by Martial, et al., Science 205, 602-606 (1979), the relatively low yield and purification difficulties have caused the price of hGH treatment to be between $8,000 and $30,000 per patient per year. Clearly a cheaper, more efficient way of producing hGH with higher yield would be beneficial both for patients and for use in the initiation of new studies to test for additional properties of hGH.
  • a proposed alternative method of production of GH is through expression in transgenic animals.
  • expression of the hormone in transgenic animals incorporating the gene for growth hormone has had a number of unexpected side effects.
  • pigs containing the gene for bGH in combination with an inducible metallothionein promoter as described by Ramabhadran, et al., in Gene 38, 111-118 (1985)
  • Transgenic mice having the gene for hGH fused with mouse metallothionein I promoter were infertile, as reported by A. Bartke, et al., 121-124 (1988). See also Kyung-Kwang, et al., Korean J. Anim. Sci.
  • tissue specific promoter for example, a cost effective alternative to production of recombinant hGH in bacteria would be its production in the milk of transgenic farm animals.
  • tissue specific promoter for a highly expressed gene product, one can achieve specific expression of the gene of interest in tissues appropriate to the regulatory sequences.
  • hGH human growth hormone
  • Figure 1 is a schematic of the construction of the pWAPhGH fusion vector, containing the WAP tissue specific promoter in combination with the gene for hGh.
  • transgenic mice expressing human growth hormone in their mammary glands which can be isolated and purified for use as a pharmaceutical is described in detail below can, with minor variations, be used to incorporate the same genes and tissue specific promoters into animals of others species, such as rats, rabbits, pigs, sheep, and cows, for expression and purification of human growth hormone.
  • genes for growth hormones of other origin such as bovine or porcine growth hormone, can be incorporated into similar vectors and inserted into the genome of the desired species.
  • the production of the growth hormone in the transgenic animals has a number of advantages, including normal glycosylation and absence of bacterial contaminants, unlike recombinant growth hormone produced by bacterial fermentation processes.
  • pmWAPTSI containing EcoRI-BamHI fragment of mouse WAP promoter obtained from Dr. Lothar Hennighausen and described by Pittices, et al., in Proc.Natl.Acad.Sci. 85, 5874-5878 (1988), was cut with Pvul and BamHI and ligated to pOGH cleaved with Pvul and BamHI.
  • pOGH contains the DNA sequences coding for hGH and its polyadenylation signal. The resulting plasmid pWAPhGH was isolated after transformation into E.
  • pWAPhGH was digested with EcoRI and the 4754 bp fragment containing the WAPhGH fusion gene was isolated on 1% agarose gel followed by electroelution in a dialysis bag, as described by Maniatis, et al. (1982). The eluted DNA was precipitated, redissolved in water and purified by passing through an elutip-D column as per the instructions of the manufacturer (Schleicher and Schuell, Inc., Keene, NH). The purified DNA was dissolved in 5mM Tris (pH 7.4) and 0.1 mM EDTA at 3 ⁇ g/ml concentration for microinjection.
  • mice were obtained from Charles River Laboratories, Boston, MA and Jackson Laboratories, Maine.
  • Reagents such as bovine serum albumin, gelatin, and pronase were obtained from Sigma Chemical Co., St. Louis, MO.
  • Hormones for superovulation, PMS and hCG, were obtained from Organon, Inc., NJ.
  • Hyaluronidase was purchased from Sigma.
  • Restriction enzymes were obtained from Biolabs, Beverly, MA.
  • the micromanipulator made by Nara Shige, USA, Inc., Rainin Instruments Co., Woburn, MA, was used to microinject DNA into the pronuclei.
  • DMEM, fetal bovine serum, and DPBS were supplied by GIBCO Laboratories, Gaithersville, MD.
  • Pronuclear embryos were recovered from B6D2 female mice mated to CDI males. Females were treated with pregnant mare serum, PMS, (5 IU) to induce follicular growth and human chorionic gonadotropin, hCG (51 U) to induce ovulation. Embryos were recovered in a Dulbecco's modified phosphate buffered saline (DPBS) and maintained in Dulbecco's modified essential medium (DMEM) supplemented with 10% fetal bovine serum.
  • DPBS Dulbecco's modified phosphate buffered saline
  • DMEM Dulbecco's modified essential medium
  • Microinjections were performed using Narishige micromanipulators attached to a Nikon diaphot microscope. Embryos were held in 100 microliter drops of DPBS under oil while being microinjected. DNA solution was microinjected into the largest visible male pronucleus. Successful injection was monitored by swelling of the pronucleus.
  • tail samples were excised for DNA analysis.
  • the tail samples were digested by incubating overnight at 55°C nutator in the presence of 0.7 ml 50 mM Tris, pH 8.0, 100 mM EDTA, 0.5% SDS and 350 ⁇ g of prokienase K.
  • the digested material was extracted once with equal volume of phenol and once with equal volume of phenol:chlorofo ⁇ n (1:1 mixture).
  • the superaatants were mixed with 70 ⁇ l 3 M sodium acetate (pH 6.0) and the DNAs were precipitated by adding equal volume of 100% ethanol.
  • the DNAs were spun down in a microfuge, washed once with 70% ethanol, dried and dissolved in 100 ⁇ L TE buffer (10 mM Tris, pH 8.0 and 1 mM EDTA). 10 to 20 ⁇ l of DNAs were cut with BamHI and Bglll or EcoRI. electrophoresed on 1% agarose gels, blotted onto nitrocellulose paper and hybridized with 32 P-labeled hGH DNA sequences. Transgenic animals were identified by autoradiography.
  • transgenic female mice were mated to CDI males. At five days following parturition milk samples were taken and assayed for hGH. At six to seven weeks of age transgenic males were mated to two CDI females. The Fl litters were analyzed for transgene. Four positive females were kept and mated at five weeks of age. At five days following parturition milk samples were assayed for hGH.
  • Milk samples (50-200 ⁇ l) were collected from anesthetized mice injected with 0.05 units of oxytocin, an inducer of lactation. The milk was collected in a glass capillary with the aid of mammaiy palpation.
  • Mouse #27 is producing hGH at the rate of 970 ng/ml
  • Stable lines of transgenic animals expression hGH in their milk are produced by mating the females expressing the gGH in their milk at the highest levels and by mating the offspring of the transgenic males.

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  • Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
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  • Endocrinology (AREA)
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  • Gastroenterology & Hepatology (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Animal Husbandry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

On a lié de l'ADN codant pour une hormone de croissance humaine à un fragment de promoteur de protéine d'acide de lactosérum puis on l'a micro-injecté dans des ÷ufs de souris fécondés. On a accouplé les femelles des souris transgéniques résultantes. Après l'achèvement de la gestation et la naissance de la portée, on a analysé le lait des mères et on a découvert qu'il contient l'hormone de croissance humaine.
PCT/US1990/005130 1989-09-11 1990-09-11 Production d'hormone de croissance dans le lait d'animaux transgeniques WO1991003551A1 (fr)

Applications Claiming Priority (2)

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US405,452 1982-08-05
US40545289A 1989-09-11 1989-09-11

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2677652A1 (fr) * 1991-06-12 1992-12-18 Agronomique Inst Nat Rech Procede de preparation d'une proteine d'interet dans le lait d'un animal transgenique, produit obtenu et cellule eucaryote utilisee.
US5739407A (en) * 1991-08-19 1998-04-14 Symbicom Aktiebolag Human β-casein, process for producing it and use thereof
US5780009A (en) * 1995-01-20 1998-07-14 Nexia Biotechnologies, Inc. Direct gene transfer into the ruminant mammary gland
US5965788A (en) * 1992-06-12 1999-10-12 Institut National De La Recherche Agronomique Transgenic non-human mammal comprising a rabbit WAP promoter
WO2000004169A1 (fr) * 1998-07-17 2000-01-27 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Nouvel homologue de caspase
US6222094B1 (en) 1992-01-23 2001-04-24 Symbicom Aktiebolag Transgenic non-human mammal expressing the DNA sequence encoding kappa casein mammary gland and milk
US6268545B1 (en) 1991-06-12 2001-07-31 Institut National De La Recherche Agronomique Transgenic non-human mammal comprising a rabbit WAP promoter, uses thereof, and a DNA construct comprising the rabbit WAP promoter
US7718845B2 (en) 2003-09-30 2010-05-18 Sterrenbeld Biotechnologie North America, Inc. Production of growth hormone in the milk of a transgenic bovine and methods of purification of the growth hormone from the milk

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101527528B1 (ko) * 2012-09-19 2015-06-19 한국표준과학연구원 가용성 재조합 단백질의 생산, 추출 및 정제 방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988001648A1 (fr) * 1986-08-28 1988-03-10 Immunex Corporation Expression de proteines heterologues par des mammiferes transgeniques en lactation
US4873316A (en) * 1987-06-23 1989-10-10 Biogen, Inc. Isolation of exogenous recombinant proteins from the milk of transgenic mammals

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988001648A1 (fr) * 1986-08-28 1988-03-10 Immunex Corporation Expression de proteines heterologues par des mammiferes transgeniques en lactation
US4873316A (en) * 1987-06-23 1989-10-10 Biogen, Inc. Isolation of exogenous recombinant proteins from the milk of transgenic mammals

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BIO/TECHNOLOGY, Volume 5, issued November 1987, (Clinton, USA), GORDON et al., "Production of Human Tissue Plasminogen Activator in Transgenic Mouse Milk", pages 1183-1187. *
GENES AND DEVELOPMENT, Volume 1, issued 1987, (Cold Spring Harbor, USA), PINKERT et al., "An Albumin Enhancer Located to kb Upstream Functions Along with its Promoter to Direct Efficient, Liver-Specific Expression in Transgenic Mice", pages 268-276. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, Volume 84, issued March 1987, (Washington, USA), ANDRES et al., "Ha-ras Oncogene Expression Directed by a Milk Protein Gene Promoter: Tissue Specificity, Hormonal Regulation, and Tumor Induction in Transgenic Mice", pages 1299-1303. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, Volume 85, issued August 1988, (Washington, USA), PITTIUS et al., "A Milk Protein Gene Promoter Directs the Expression of Human Tissue Plasminogen Activator cDNA to the Mammary Gland in Transgenic Mice", pages 5874-5878. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, Volume 85, issued December 1988, (Washington, USA), SWEETSER et al., "Transgenic Mice Containing Intestinal Fatty Acid-Binding Protein-Human Growth Hormone Fusion Genes Exhibit Correct Regional and Cell-Specific Expression of the Reporter Gene in Their Small Intestine", pages 9611-9615. *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6268545B1 (en) 1991-06-12 2001-07-31 Institut National De La Recherche Agronomique Transgenic non-human mammal comprising a rabbit WAP promoter, uses thereof, and a DNA construct comprising the rabbit WAP promoter
WO1992022644A1 (fr) * 1991-06-12 1992-12-23 Institut National De La Recherche Agronomique Production d'une proteine d'interet dans le lait d'un mammifere transgenique
EP0527063A1 (fr) * 1991-06-12 1993-02-10 Institut National De La Recherche Agronomique Production d'une protéine d'intérêt dans le lait d'un mammifère transgènique
FR2677652A1 (fr) * 1991-06-12 1992-12-18 Agronomique Inst Nat Rech Procede de preparation d'une proteine d'interet dans le lait d'un animal transgenique, produit obtenu et cellule eucaryote utilisee.
US5739407A (en) * 1991-08-19 1998-04-14 Symbicom Aktiebolag Human β-casein, process for producing it and use thereof
US6222094B1 (en) 1992-01-23 2001-04-24 Symbicom Aktiebolag Transgenic non-human mammal expressing the DNA sequence encoding kappa casein mammary gland and milk
US6232094B1 (en) 1992-01-23 2001-05-15 Symbicom Aktiebolag DNA encoding human κ casein and process for obtaining the protein
US5965788A (en) * 1992-06-12 1999-10-12 Institut National De La Recherche Agronomique Transgenic non-human mammal comprising a rabbit WAP promoter
US5780009A (en) * 1995-01-20 1998-07-14 Nexia Biotechnologies, Inc. Direct gene transfer into the ruminant mammary gland
WO2000004169A1 (fr) * 1998-07-17 2000-01-27 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Nouvel homologue de caspase
US6759227B2 (en) 1998-07-17 2004-07-06 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Caspase homologue
US7718845B2 (en) 2003-09-30 2010-05-18 Sterrenbeld Biotechnologie North America, Inc. Production of growth hormone in the milk of a transgenic bovine and methods of purification of the growth hormone from the milk
US7807862B2 (en) 2003-09-30 2010-10-05 Sterrenbeld Biotechnologie North America, Inc. Transgenic bovine comprising human growth hormone in its serum and methods of making

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JPH06339331A (ja) 1994-12-13
JPH04506751A (ja) 1992-11-26
CA2065866A1 (fr) 1991-03-12

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