WO1997034628A1 - Milk of transgenic animals containing human alpha1-antitrypsin and use of human alpha1-antitrypsin to treat bile acid related diseases - Google Patents
Milk of transgenic animals containing human alpha1-antitrypsin and use of human alpha1-antitrypsin to treat bile acid related diseases Download PDFInfo
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- WO1997034628A1 WO1997034628A1 PCT/SE1997/000465 SE9700465W WO9734628A1 WO 1997034628 A1 WO1997034628 A1 WO 1997034628A1 SE 9700465 W SE9700465 W SE 9700465W WO 9734628 A1 WO9734628 A1 WO 9734628A1
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- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
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- 229940106780 human fibrinogen Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
- C07K14/8121—Serpins
- C07K14/8125—Alpha-1-antitrypsin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/20—Milk; Whey; Colostrum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
-
- 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
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
Definitions
- Pi ZZ is one of the most common known genetic diseases with a frequen ⁇ cy in Sweden of 1 in 1600 and in northern Europe of about 1/2000. Half of these individuals develop pulmonary emphysema with a mean age at onset of 32 years for smokers and 51 years for non-smokers. PiMZ heterozygotes have considerably milder disease, but non-smoking Pi MZ individuals also experience a significant decrease in lungfunction compared with normal Pi MM controls which was verified in a prospective study from mean age 30 to 40 years.
- Pi ZZ ⁇ -AT which differs from the normal Pi M ⁇ -AT by either a single amino acid change (342 Glu->Lys) or by this change in combination with a neutral substitution (213 Val->Ala) aggregates within the endoplasmic reticulum of hepatocy ⁇ tes causing a secretory defect and a deficiency of the circulating inhibitor. This aggregation may be due to a spontaneous concentration- and temperature dependent polymerization of the Pi Z protein, although a more complex mechanism is suspected 5 .
- the Mayo Clinic has found a significant overrepresentation of Pi ZZ patients among those with fibromuscular dysplasia. Reports on a theoretical association with aortic aneurysms conflict, but arterial aneurysms have complicated liver transplan ⁇ tation in some pediatric cases. An increased frequency of the Pi MZ phenotype is also seen among patients with rheumatoid arthritis.
- mice were expected to develop liver disease only if the mtracellular inclusions were responsible because they continued to produce their own endogenous "mouse inhibitors" and therefore have no cir ⁇ culatory deficiency.
- serpins have been shown to have specific transport functions: corticosteroid binding globulin for cortisol, thyroxin binding globulin for thyroxin; and antithrombin III for heparin, and may release their transported ligand upon cleavage at the active site by a serine protease. No transport function has been thus far identified for ct]_-AT.
- This polymeric complex is furthermore inactive as an in ⁇ hibitor of ⁇ -AT' s preferred target enzyme, neutrophile elastase.
- Another interesting observation made when puri ⁇ fying ⁇ -AT from a PiZZ patient with gemfibrozil treat- ment for hyperlipidemia was that gemfibrozil also formed a stable complex with PiZ ⁇ -AT, ablating its capacity to inhibit elastase 13 .
- ⁇ -AT or proteolytic peptides derived from ⁇ _-AT have previously been identified in the bile.
- c -AT has three mutually exclusive functions: 1) ⁇ ]_-AT inhibits the proteolytic effect of target serine proteases. 2) c -AT appears to form complexes with a number of steroids and steroid-like hydrophobic com ⁇ pounds, and functions as a transport vehicle for these substances in analogy to corticosteroid binding globulin. Similarity in structure with sulfate transporters (PROSITE databasePDOC00870) suggests that ⁇ ] _-AT may also be active in the metabolic conjugation or transformation of such substances. Transport may be directed to specific cells via the SEC receptor, for further detoxification or metabolism.
- Native ⁇ _-AT is capable of complexing free immunoglobulin lambda light chains 14 and ⁇ i-antichymo- trypsin binds ⁇ -amyloid peptide 15 .
- Peptides may be insert ⁇ ed into the beta sheet of ct_-AT, occupying the position normally available for sheet 4A of ⁇ -AT after its inter ⁇ action with its target enzyme (fig. I) 5 .
- Fig. 1 Shows the crystalline structure of human ⁇ AT (a) and chicken ovalbumin (b) .
- ⁇ _-AT was crystallized after cleavage by trypsin at the active site Pl-Pl' .
- the strand s4A is the active site loop (cfr b) , which upon cleavage is inserted into the ⁇ -sheeted plate A 5 .
- the hydrophobic core in which steroid-like substances are transported is marked " * " .
- Binding to Pi Z ⁇ x -AT in the endoplasmic reticulum induces polymerization and simultaneoulsy prevents c ⁇ -AT from performing its other beneficial functions.
- the increasing total body burden of hydrophobic bile acids in liver disease results in the formation of complexes with circulating o ⁇ -AT, inactiva ⁇ tion of its protease inhibitor function, and possibly spontaneous polymerization in blood vessels.
- the end result may be vasculitis and glomerulonephritis.
- Vitamin E deficiency and excess hydrophobic bile acids exert a combined oxidative stress on the hepatocyte, which is further potentiated by the accumulation of iron and copper in cholestatic disease 18 .
- the invention describes the use of human ⁇ _-anti- trypsin as a foodstuff or as a medicament, utilizing its capacity to bind hydrophobic substances and steroids and steroid-like substances, and transporting such substances in biological systems. It does not exclude the use of a_- antitrypsin for the transport of other substances after demonstration of specific binding to such substances.
- a_- antitrypsin for the transport of other substances after demonstration of specific binding to such substances.
- it describes the direct oral administra tion of the milk of transgenic animals containing abundant amounts of human ct]_-AT. Such treatment will reinstate a normal physiological function, i.e. to reduce the total body load of bile acids by increasing their gastrointes ⁇ tinal elimination.
- bile acid related diseases such as all cholestatic liver diseases, and bile-reflux gastritis.
- Such treatment is expected to be particularly beneficial in cases of neonatal cholestasis, as newborns circulate large quanti ⁇ ties of hydrophobic bile acids which cause liver injury and may contribute to injury of other tissues. It will be protective in cases where bile acids cause tissue injury such as vasculitis, glomerulonephritis, and inflammatory bowel disease. It will be beneficial against diarrhoea in intestinal bacterial overgrowth and bile acid malabsorp- tion. Increased gastrointestinal elimination of the steroid structure may also reduce the total body load of cholesterol and thus be efficient in the treatment of hyperlipidemia.
- Subsequent longterm supplements should be beneficial to prevent the slow, sub- clinical development of liver disease in Pi ZZ indivi ⁇ duals, and to prevent vascular complications in liver transplanted Pi ZZ patients.
- Availability of a reasonable therapeutic alternative should also increase motivation for early diagnosis of the condition, its longterm follow up and treatment.
- Hydrophobic bile acids should be highly detrimental in other cholestatic liver diseases, producing a vicious circle with increased hepatocellular injury due to the "bad" quality of the bile.
- diseases include intrahepatic biliary atresia, primary biliary cirrhosis, sclerosing cholangitis, and possibly secondary injury due to the cholestatic compo- nent of other metabolic diseases such as hemochromatosis and Wilson's Disease. All of these conditions should also be alleviated by the same treatment, regardless of access to or inavailability of a primary causal therapy.
- Such treatment may even have a beneficial effect on the pro- gress of all forms of cirrhosis, including alcoholic liver cirrhosis, in which abnormal bile acid pools have developed secondary to liver disease.
- the delivery of such a foodstuff or medicament supplemented with the fat soluble vitamins could provide a targetted delivery system using the SEC receptor and replenish deficiencies secondary to the liver disease, as well as protect against oxidative stress.
- This treament could also be effective in the liver disease associated with cystic fibrosis, and might alleviate diarrhea caused by bacte- rial overgrowth.
- ⁇ -AT as a transport vehicle for steroid-like substances is completely different from the documented therapeutic use of human ⁇ _-AT purified from plasma (Prolastin) as a protease inhibitor, in the treatment of emphysema 25-28 .
- ⁇ -AT is an example of a serine protease inhibitor which may be combined with calcitonin (to prevent proteolytic degradation of calci ⁇ tonin) and bile acid salts (to enhance percutaneous absorption) in an "easily administered percutaneous absorption composition".
- ⁇ -AT may be administered as an example of a "serine protease inhibitor of viral replication" m which administration is preferably by infusion and ⁇ -AT is intended as an antiviral drug. Nonetheless, use of ⁇ ]_-AT purified from the milk of transgenic animals is not excluded from this invention.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Cell Biology (AREA)
- Developmental Biology & Embryology (AREA)
- Virology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97914726A EP0904102A1 (en) | 1996-03-21 | 1997-03-20 | Milk of transgenic animals containing human alpha 1-antitrypsin and use of human alpha 1-antitrypsin to treat bile acid related diseases |
AU21864/97A AU2186497A (en) | 1996-03-21 | 1997-03-20 | Milk of transgenic animals containing human alpha1-antitrypsin and use of human alpha1-antitrypsin to treat bile acid related diseases |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9601091-3 | 1996-03-21 | ||
SE9601091A SE9601091L (en) | 1996-03-21 | 1996-03-21 | Use of a protein substance for the binding of steroid-like molecules |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997034628A1 true WO1997034628A1 (en) | 1997-09-25 |
Family
ID=20401887
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1997/000465 WO1997034628A1 (en) | 1996-03-21 | 1997-03-20 | Milk of transgenic animals containing human alpha1-antitrypsin and use of human alpha1-antitrypsin to treat bile acid related diseases |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0904102A1 (en) |
AU (1) | AU2186497A (en) |
SE (1) | SE9601091L (en) |
WO (1) | WO1997034628A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000030436A1 (en) * | 1998-11-19 | 2000-06-02 | Ppl Therapeutics (Scotland) Ltd. | Stabilisation of milk from transgenic animals |
WO2000044390A1 (en) * | 1999-02-01 | 2000-08-03 | John Lezdey | Treatment of bladder and gastrointestinal mastocytosis |
EP1171451A1 (en) * | 1999-04-12 | 2002-01-16 | Gradipore Limited | Separation of plasma components |
US7030289B2 (en) | 1998-11-19 | 2006-04-18 | Ppl Therapeutics (Scotland) Ltd | Stabilization of milk from transgenic animals |
US20130197085A1 (en) * | 2007-07-12 | 2013-08-01 | Hisamitsu Hayashi | Agent and method for stabilizing membrane protein |
US11229634B2 (en) | 2016-02-22 | 2022-01-25 | Novartis Ag | Methods for treating gastrointestinal disorders using FXR agonists |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988010118A1 (en) * | 1987-06-23 | 1988-12-29 | Biogen N.V. | Expression of proteins in milk |
WO1994026896A1 (en) * | 1993-05-06 | 1994-11-24 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Increased expression of alpha-1-antitrypsin in expression vectors through the inclusion of intron ii |
-
1996
- 1996-03-21 SE SE9601091A patent/SE9601091L/en not_active Application Discontinuation
-
1997
- 1997-03-20 WO PCT/SE1997/000465 patent/WO1997034628A1/en not_active Application Discontinuation
- 1997-03-20 AU AU21864/97A patent/AU2186497A/en not_active Abandoned
- 1997-03-20 EP EP97914726A patent/EP0904102A1/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988010118A1 (en) * | 1987-06-23 | 1988-12-29 | Biogen N.V. | Expression of proteins in milk |
WO1994026896A1 (en) * | 1993-05-06 | 1994-11-24 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Increased expression of alpha-1-antitrypsin in expression vectors through the inclusion of intron ii |
Non-Patent Citations (2)
Title |
---|
DIALOG INFORMATION SERVICES, File 155, Medline, Dialog Accession No. 05060910, Medline Accession No. 83293910, NEMETH A. et al., "Serum Bile Acids as Markers of Juvenile Liver Disease in Alpha 1-Antitrypsin Deficiency"; & J. PEDIATR. GASTROENTEROL. NUTR. (UNITED STATES), 1982, 1(4), p479-83. * |
DIALOG INFORMATION SERVICES, File 155, Medline, Dialog Accession No. 08907187, Medline Accession No. 94222187, JANCIAUSKIENE S. et al., "The Interaction of Hydrophobic Bile Acids with the alpha 1-proteinase Inhibitor"; & FEBS LETT., (NETHERLANDS), 25 Apr. 1994, 343(2), p141-5. * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000030436A1 (en) * | 1998-11-19 | 2000-06-02 | Ppl Therapeutics (Scotland) Ltd. | Stabilisation of milk from transgenic animals |
US7030289B2 (en) | 1998-11-19 | 2006-04-18 | Ppl Therapeutics (Scotland) Ltd | Stabilization of milk from transgenic animals |
WO2000044390A1 (en) * | 1999-02-01 | 2000-08-03 | John Lezdey | Treatment of bladder and gastrointestinal mastocytosis |
US6566331B1 (en) * | 1999-02-01 | 2003-05-20 | Alphamed Pharmaceutical Corp | Treatment of collagen related diseases |
EP1171451A1 (en) * | 1999-04-12 | 2002-01-16 | Gradipore Limited | Separation of plasma components |
EP1171451A4 (en) * | 1999-04-12 | 2003-04-02 | Gradipore Ltd | Separation of plasma components |
US20130197085A1 (en) * | 2007-07-12 | 2013-08-01 | Hisamitsu Hayashi | Agent and method for stabilizing membrane protein |
US11229634B2 (en) | 2016-02-22 | 2022-01-25 | Novartis Ag | Methods for treating gastrointestinal disorders using FXR agonists |
Also Published As
Publication number | Publication date |
---|---|
SE9601091L (en) | 1997-09-22 |
EP0904102A1 (en) | 1999-03-31 |
SE9601091D0 (en) | 1996-03-21 |
AU2186497A (en) | 1997-10-10 |
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