WO2000060943A1 - Prevention de lesions cerebrales liees a des accidents vasculaires cerebraux - Google Patents

Prevention de lesions cerebrales liees a des accidents vasculaires cerebraux Download PDF

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Publication number
WO2000060943A1
WO2000060943A1 PCT/US2000/010002 US0010002W WO0060943A1 WO 2000060943 A1 WO2000060943 A1 WO 2000060943A1 US 0010002 W US0010002 W US 0010002W WO 0060943 A1 WO0060943 A1 WO 0060943A1
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WIPO (PCT)
Prior art keywords
pro
val
ala
leu
human
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PCT/US2000/010002
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English (en)
Inventor
Kevin J. Tracey
Haichao Wang
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North Shore-Long Island Jewish Research Institute
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Filing date
Publication date
Application filed by North Shore-Long Island Jewish Research Institute filed Critical North Shore-Long Island Jewish Research Institute
Priority to AU43485/00A priority Critical patent/AU766910B2/en
Priority to EP00923342A priority patent/EP1191845A4/fr
Priority to CA002368937A priority patent/CA2368937A1/fr
Priority to JP2000610293A priority patent/JP2002541162A/ja
Priority to US09/958,585 priority patent/US7186555B1/en
Publication of WO2000060943A1 publication Critical patent/WO2000060943A1/fr

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    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention provides a method and a pharmaceutical composition useful to mitigate tissue damage associated with ischemia, particularly of the brain (stroke, brain attack) and heart (myocardial infarction, heart attack).
  • Delayed cell death in the under-perfused penumbral region is caused by a poorly understood cascade of cytotoxic mediators that kill otherwise potentially viable cells.
  • the time course of progressive brain damage within this penumbra limits the duration of the therapeutic window, and new therapeutic approaches will depend first on the identification of responsible cytotoxic mediators and secondly on the identification of antagonists that can be administered within the therapeutic window.
  • the goal of therapy for cerebral infarction is to prevent the loss of potentially viable brain tissue in the early hours after the onset of ischemia, and there is a need to identify both target mechanisms of cytotoxicity and suitable antagonist agents to minimize brain damage in stroke.
  • alpha-2HS-Glycoprotein ( ⁇ 2-HS), sometimes called human fetuin, is the human homolog of the bovine protein originally isolated as fetuin.
  • Alpha-2HS-Glycoprotein is a major protein occurring in human blood and calciferous tissues (where has been known as
  • ⁇ 2-HS has been grouped with the fetuins, a family of proteins that occur in fetal plasma in high concentrations. Native ⁇ 2-HS undergoes a series of posttranslational modifications including proteolytic processing, multiple N-glycosylations and O-glycosylations, sulfation of the carbohydrate side chains, and phosphorylation, such that slightly differing mature forms may be present.
  • 2-HS is generally considered to comprise two polypeptide chains, the A chain (282 amino acids) with five internal disulfide bridges forming it into a series of loops, and the B chain (27 amino acids) linked by a single disulfide bridge to the A chain.
  • Human fetuin, or ⁇ 2-HS is generally considered to arise from a single mRNA transcript encoding a 367 amino acid peptide known as the "alpha-2-HS-glyco ⁇ rotein precursor" (SEQ ID NO. 1).
  • Amino acids 1-18 (SEQ ID NO. 2) comprise a signal sequence domain.
  • Amino acids 19-300 comprise the ⁇ 2-HS-glycoprotein A chain domain (SEQ ID NO. 3).
  • Amino acids 341-367 comprise the ⁇ 2-HS-glycoprotein B chain domain (SEQ ID NO. 4).
  • amino acids 301-340 comprise a 40 amino acid connecting sequence (SEQ ID NO. 5) that is not present in the mature form, although single chain forms of ⁇ 2-HS have been isolated (Jahen-Dechent et al., Eur. J. Biochem. 226:59-69, 1994).
  • Bovine fetuin occurs as a single chain, globular 341 amino acid polypeptide (amino acids 19-359 of the 359 amino acid bovine fetuin precursor) with six internal disulfide bonds and three N-linked and two O-linked oligosaccharides (SEQ ID NO. 6).
  • Primary amino acid sequence and the position of cysteine residues are well conserved across species, e.g., human, bovine, sheep, rat and mouse (Dziegielewska et al., J. Biol. Chem.
  • Fetuin ( ⁇ 2-HS) levels in human plasma are regulated in the manner of a negative acute phase reactant (Lebreton et al., J. Clin. Invest. 64:1118, 1979).
  • IL-1 was shown to suppress ⁇ 2-HS transcript levels in cultured hepatocytes (Akhoundi et al., J. Biol Chem. 268: 15925, 1994).
  • ⁇ 2-HS appears to be expressed in bone because transcripts have been detected in both chondrocytes and osteoblasts (Yang et al.,
  • ⁇ 2-HS influences the mineral phase of bone.
  • the ⁇ 2-HS glycoprotein is the human homolog of fetuin and is secreted in high levels by adult liver into the peripheral circulation (Triffitt et al., Nature 262:226, 1976).
  • ct2-HS Human fetuin
  • ct2-HS Human fetuin
  • the sugar moiety directly attached to the ⁇ 2-HS polypeptide is usually a ⁇ -acetylglucosamine residue.
  • the terminal sugar residue is usually a sialic acid, in particular a ⁇ -acetylneuraminic acid ( ⁇ A ⁇ A) residue, which bears a net negative charge.
  • Fetuin ( ⁇ 2-HS) is also a carrier protein for growth factors and cytokines.
  • the synthesis of human ⁇ 2-HS -glycoprotein is down-regulated by cytokines (hIL-l ⁇ , hIL-6) (Lebreton et al., J. Clin. Invest. 64:1118-1129, 1979).
  • Human fetuin ( ⁇ 2-HS) levels are decreased (25-50%) in trauma patients (van Oss et al, J. Trauma 15:451, 1975).
  • ⁇ 2-HS is structurally related to the cystatins and kininogens.
  • “Fetuin” as used herein refers, in the context of the human protein, to the glycoprotein referred to variously as “ ⁇ 2-HS-glycoprotein” or “ ⁇ 2-Z-globulin” or “human fetuin” or “human fetuin glycoprotein,” and in broader context to any of the fetuin family of proteins, with members occurring in various species and closely related in sequence to bovine fetuin and human ct2-HS. Two common alleles are known for ⁇ 2-HS: one has threonine at position 248 and 256, the other has methionine at 248 and serine at 256.
  • fetuin or " ⁇ 2-HS” shall correspondingly include use of allelic variants, glycosylation, sulfation and phosphorylation variants, reduced and native forms, precursor and proteolytically processed forms, and sequence variants substantially homologous to the polypeptides described by SEQ ID NO.'s 1-6 or to the fetuins of other (non-human) species, and fragments of any of the above.
  • allelic variants glycosylation, sulfation and phosphorylation variants, reduced and native forms, precursor and proteolytically processed forms, and sequence variants substantially homologous to the polypeptides described by SEQ ID NO.'s 1-6 or to the fetuins of other (non-human) species, and fragments of any of the above.
  • Such variants whether naturally occurring, intentionally introduced or spontaneously arising, are conveniently tested for activity (and thereby evaluated for clinical utility) in accordance with the Detailed Description and Examples described herein.
  • the present invention arose out of a series of experiments wherein brain damage (cell death) subsequent to induced focal ischemia was found to be ameliorated by treatment with the glycoprotein ⁇ 2-HS.
  • the present invention identifies for the first time the cellular and tissue protective effects of administering ⁇ 2-HS in the setting of ischemia.
  • the present invention further provides methods and pharmaceutical compositions for preventing tissue damage in ischemia, particularly brain damage attendant to stroke or cerebral ischemia, comprising administering an effective amount of an ⁇ 2-HS glycoprotein.
  • the ⁇ 2-HS glycoprotein is a human ⁇ 2-HS glycoprotein comprising a primary sequence according to SEQ ID NO. 1 through SEQ ID NO. 5 or a shorter fragment thereof.
  • homologous sequence variants are also useful in this regard, particularly such homologous glycoproteins as have effects quantitatively indistinguishable from ⁇ 2-HS in the assays described herein.
  • variant glycoproteins are conveniently produced according to techniques of molecular biology well-known in the art and are readily compared to human ⁇ 2-HS glycoprotein in the assays described herein, or in comparable assays for cellular or tissue protection in the setting of ischemia.
  • Stroke ischemia and associated tissue damage
  • Stroke ischemia and associated tissue damage
  • cerebral infarction cerebrovascular accident
  • thrombotic stroke embolic stroke
  • occlusive cerebrovascular lesion apoplexy (of various types)
  • apoplectic stroke paralytic stroke, intracranial hemorrhage, hemorrhagic stroke, ruptured aneurysm, post-traumatic stroke, transient ischemic attack, and stroke syndrome.
  • heart attack may arise variously, giving rise to such representative clinical characterizations as: cardiac infarction, myocardial infarction (various types), coronary artery occlusion, coronary thrombosis, coronary embolism, periarteritis nodosa, and obliterating endarteritis.
  • cardiac infarction myocardial infarction (various types)
  • coronary artery occlusion coronary thrombosis
  • coronary embolism periarteritis nodosa
  • obliterating endarteritis obliterating endarteritis.
  • other organs and tissues may become afflicted by ischemia involving, among other conditions, anemic, pale, white or bland infarction, various embolic disorders including embolic infarction, various thrombotic disorders including thrombotic infarction, hemorrhagic or red infarction, and coagulation necrosis. Any of these conditions of ischemia, and their
  • Figure 1 demonstrates the expression of ⁇ 2-HS in infarct regions of brain cortex from rats subjected to experimental focal cerebral ischemia.
  • Figure 1 A is a Western blot showing ⁇ 2-HS protein expression in regions of infarct induced in the brain cortex of rats subjected to experimental focal ischemia.
  • Lane 1 sampled from normal brain; lane 2, two hours post onset of ischemia; lane 3, six hours post onset of ischemia; lane 4, 24 hours post onset of ischemia; lane 5, 48 hours post onset of ischemia; lane 6, 96 hours post onset of ischemia.
  • Figure IB is a plot of scanning densitometric values derived from the Western blots of Figure 1A plotted against hours post onset of ischemia.
  • Figure 2 shows the effects of ⁇ 2-HS treatment on infarct size in experimental focal cerebral ischemia.
  • ⁇ 2-HS treatment significantly reduced infarct volume when administered intravenously 15 min after the induction of ischemia.
  • Histograms represent infarct volume as a percentage of half cortical volume 24 hours after onset of ischemia.
  • Figure 4 shows a time course of the therapeutic benefit of ⁇ 2-HS treatment in stroke.
  • the histograms represent cortical infarct volume as a percentage of half-cortex volume at 24 hours after induction of focal cerebral ischemia in rats.
  • ⁇ 2-HS was administered at a dose of 50 mg /kg intravenously 60 min (cc2-HS 1), 30 min ( ⁇ 2-HS 2) or 15 min ( ⁇ 2-HS 3) after induction of experimental focal cerebral ischemia in rats.
  • the present invention is based on the discovery that a human plasma glycoprotein, ⁇ 2- HS, is beneficial in preventing tissue damage associated with ischemia, and specifically in treating stroke.
  • ⁇ 2- HS a human plasma glycoprotein
  • fetuin was discovered more than 50 years ago as a component of fetal bovine serum, and subsequently found to share high homology with a human ⁇ 2-HS counterpart ( ⁇ 2-HS-glycoprotein), no role for ⁇ 2-HS in the natural history, etiology or treatment of stroke (cerebral infarction, cerebral ischemia, brain attack) or other tissue ischemia had been suspected.
  • the present invention provides novel methods ( ⁇ 2-HS administration as adjunctive or monotherapy) and pharmaceutical compositions (comprising ⁇ 2-HS or glycoprotein sequence variants) to treat and mitigate against tissue damage in ischemia, particularly in stroke and heart attack.
  • Effective doses of the therapy are determined by routine procedures in the art with reference to the findings described herein, and may be formulated in suitable pharmacological carriers for administration by any appropriate means including, but not limited to, injection (such as, intravenous, intramuscular, intrathecal, and intracranial) and other means available within the pharmaceutical arts.
  • Treatment may be accomplished by administration of the ⁇ 2-HS glycoprotein alone or in a pharmaceutical composition where it is mixed with suitable carriers or excipients to treat tissue ischemia or mitigate against ischemic tissue damage.
  • ⁇ 2-HS is systemic to provide organ sites of treatment including the brain, CNS, myocardium, or other organ site experiencing ischemia.
  • a therapeutically effective dose refers to that amount of the active agent sufficient to treat tissue ischemia or to mitigate against ischemic tissue damage.
  • Therapeutically effective doses may be administered alone or as adjunctive therapy in combination with other treatments or supportive measures for tissue ischemia, particularly for stroke or for heart attack.
  • ⁇ 2-HS may be co-administered with spermine or otherwise in accordance with the teachings of USSN: 08/780,31 1 (filed ), the disclosure of which is incorporated herein by reference in its entirety. Techniques for the formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Company, Easton, PA, latest edition.
  • Rats were subjected to a microsurgical right frontal craniotomy and permanent occlusion of the middle cerebral artery as described previously in detail (Zimmerman, et al., Pro c Natl Acad Sci USA, 92:3744-3748, 1995; Cocroft, et al., Stroke, 27: 1393-1398, 1996). Briefly, the ipsilateral common carotid artery was ligated and divided, the middle cerebral artery was coagulated and divided distally to the lenticulostriate branch, and the contralateral common carotid artery temporarily occluded (one hour). The onset of ischemia was defined as the time the middle cerebral artery was cut.
  • ischemic brain is known to contain elevated levels of polyamines, and since ⁇ 2- HS is known to enhance the anti-inflammatory properties of spermine (USSN 08/932,871, incorporated herein in its entirety), we sought to assess the therapeutic benefit of ⁇ 2-HS treatment in stroke.
  • rats subjected to experimental focal cerebral ischemic challenge suffered smaller infarcts if they were treated intravenously with ⁇ 2-HS at 50 mg/kg than if they were untreated. Under these conditions, treatment with asialofetuin exacerbated stroke damage.
  • This brain damage-ameliorating effect of ⁇ 2-HS treatment is predictive of a therapeutic benefit in response to ⁇ 2-HS treatment in the context of human stroke or cerebrovascular accident, and in other conditions of ischemic tissue damage (e.g., heart attack).
  • Example 3 Inhibition of brain damage by ⁇ 2-HS treatment is dose-dependent
  • Rats were subjected to unilateral permanent focal cerebral ischemia and treated intravenously with ⁇ 2-HS at 50 mg/kg at different latencies after onset of ischemia: 15 minutes, 30 minutes or 60 minutes after permanent occlusion of the middle cerebral artery. As shown in Figure 4, treatment with ⁇ 2- HS within 30 minutes following the onset of ischemia was of the greatest benefit in minimizing stroke damage.
  • Brain tissues were fixed by sequential intracardiac perfusion with 0.05 M phosphate buffer saline (PBS, pH 7.4) containing 0.1% sodium nitrate and heparin, followed by infusion with 2% paraformaldehyde in 0.1M PBS (pH 7.4) containing 5% sucrose (for TNF staining), or 4% paraformaldehyde in 0.1M PB (pH 7.4, for ⁇ 2-HS staining). Following perfusion, the brains were removed and stored in the same fixative solution for 15 min at 4 °C (staining for TNF) and overnight (staining for ⁇ 2-HS) and then transferred to a solution of 20% sucrose in PBS overnight, at 4 °C.
  • PBS phosphate buffer saline
  • the frozen sections of the samples were cut para-sagittally and coronally in alternate series of 20 ⁇ m thick with the cryostat.
  • the sections were attached to gelatin-coated slides, air dried, and stored at -20 °C until use. After quenching endogenous peroxidase activity with 0.3% H 2 O solution, sections were incubated in a 1:20 dilution of either normal horse or goat serum (ACCURATE) for 1 hour.
  • ACCURATE normal horse or goat serum
  • DBS avidin-biotinylated horseradish peroxidase system
  • EDI which is a mouse monoclonal IgG antibody (Accurate Chemical & Scientific Corp.), was used at a dilution of 1 :2000; a polyclonal rabbit antimouse TNF- , (RDI), was used at dilution of 1 TOO.
  • biotinylated horse anti-mouse adsorbed (for EDI) and biotinylated goat anti-rabbit (for TNF- ⁇ antisera) antibodies (1 :150 dilution in PBST) for 1 hour at 25 °C; avidin-biotinylated horseradish peroxidase complex (DBS) in PBST, pH 7.2, for 1 hour at 25 °C; and a 0.1 M solution of 3,3'-diaminobenzidine (DAB) in 0.05 M Tris-HCl buffer, pH 7.4, for 10 min, to which bad been added 0.75 ml of 3% HO 2 (for EDI), or 3% 3-amino-9-ethylcarbazole (AEC) in N,N-dimethylformamide (for TNF- ⁇ and fetuin), for 15 min.
  • TNF ⁇ 2-HS suppressed TNF production.
  • TNF was not detected in brain sections of normal brain by immunostaining with anti-TNF antibodies. After the onset of cerebral ischemia in the present model, however, TNF immunoreactivity was significantly increased in the ischemic core and penumbra area, but remained undetectable in the contralateral hemisphere.
  • Most TNF- ⁇ positive cells in the ipsilateral cortical neuronal layer showed typical morphology of neuronal cells; whereas some TNF-positive cells in the surrounding ventricles, the out most layer of the core, and the corpus collosum in the ischemic hemisphere revealed morphology of microglia cells.
  • TNF-positive neronal cells were located in the focal ischemic region (as opposed to the perifocal ischemic area).
  • the mechanism of the therapeutic activity is thought to be at least partially through down-regulation of TNF expression during ischemia.
  • MOLECULE TYPE protein
  • HYPOTHETICAL no
  • ANTI-SENSE no
  • FRAGMENT TYPE (vi) ORIGINAL SOURCE : ⁇ 2 -HS -glycoprotein precursor
  • ORGANISM human (ix) SEQUENCE DESCRIPTION: SEQ ID NO : 1: Met Lys Ser Leu Val Leu Leu Leu Cys Leu Ala Gin Leu Trp Gly Cys

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des procédés et des compositions pharmaceutiques de la glycoprotéine humaine fétuine ou α2-HS glycoprotéine ou ses fragments utiles pour limiter les lésions tissulaires associées à l'ischémie, et plus particulièrement à des accidents vasculaires cérébraux ou à l'infarctus du myocarde.
PCT/US2000/010002 1999-04-13 2000-04-13 Prevention de lesions cerebrales liees a des accidents vasculaires cerebraux WO2000060943A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU43485/00A AU766910B2 (en) 1999-04-13 2000-04-13 Prevention of brain damage in stroke
EP00923342A EP1191845A4 (fr) 1999-04-13 2000-04-13 Prevention de lesions cerebrales liees a des accidents vasculaires cerebraux
CA002368937A CA2368937A1 (fr) 1999-04-13 2000-04-13 Prevention de lesions cerebrales liees a des accidents vasculaires cerebraux
JP2000610293A JP2002541162A (ja) 1999-04-13 2000-04-13 発作による脳障害防止法
US09/958,585 US7186555B1 (en) 1999-04-13 2000-04-13 Prevention of brain damage in stroke

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12928899P 1999-04-13 1999-04-13
US60/129,288 1999-04-13

Publications (1)

Publication Number Publication Date
WO2000060943A1 true WO2000060943A1 (fr) 2000-10-19

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PCT/US2000/010002 WO2000060943A1 (fr) 1999-04-13 2000-04-13 Prevention de lesions cerebrales liees a des accidents vasculaires cerebraux

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EP (1) EP1191845A4 (fr)
JP (1) JP2002541162A (fr)
AU (1) AU766910B2 (fr)
CA (1) CA2368937A1 (fr)
WO (1) WO2000060943A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1401471A2 (fr) * 2001-05-22 2004-03-31 Jenny Yu Composition et methode de traitement de cellules
US7344721B2 (en) * 1997-12-18 2008-03-18 David Tsai Polypeptide for the treatment of cancer and a method for preparation thereof
WO2021180884A1 (fr) 2020-03-11 2021-09-16 Universitaet Bern Fétuine a pour le traitement de troubles rénaux

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4426929B2 (ja) * 2004-03-25 2010-03-03 株式会社アミンファーマ研究所 脳卒中・無症候性脳梗塞のスクリーニング方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5972924A (en) * 1995-01-20 1999-10-26 Maas Biolab, Llc Treatment of cerebral ischemia and cerebral damage with neuroprotective agents

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9113164D0 (en) * 1991-06-18 1991-08-07 Ici Plc Pharmaceutical agent

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5972924A (en) * 1995-01-20 1999-10-26 Maas Biolab, Llc Treatment of cerebral ischemia and cerebral damage with neuroprotective agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1191845A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7344721B2 (en) * 1997-12-18 2008-03-18 David Tsai Polypeptide for the treatment of cancer and a method for preparation thereof
EP1401471A2 (fr) * 2001-05-22 2004-03-31 Jenny Yu Composition et methode de traitement de cellules
EP1401471A4 (fr) * 2001-05-22 2005-12-28 Jenny Yu Composition et methode de traitement de cellules
WO2021180884A1 (fr) 2020-03-11 2021-09-16 Universitaet Bern Fétuine a pour le traitement de troubles rénaux

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Publication number Publication date
EP1191845A1 (fr) 2002-04-03
AU766910B2 (en) 2003-10-23
JP2002541162A (ja) 2002-12-03
EP1191845A4 (fr) 2002-07-17
AU4348500A (en) 2000-11-14
CA2368937A1 (fr) 2000-10-19

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