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WO1999036536A9 - Methodes et compositions permettant de modifier la sensibilite des tissus face aux lesions immunitaires, a la mort cellulaire programmee et a la clairance par le systeme reticulo-endothelial - Google Patents

Methodes et compositions permettant de modifier la sensibilite des tissus face aux lesions immunitaires, a la mort cellulaire programmee et a la clairance par le systeme reticulo-endothelial

Info

Publication number
WO1999036536A9
WO1999036536A9 PCT/US1999/001087 US9901087W WO9936536A9 WO 1999036536 A9 WO1999036536 A9 WO 1999036536A9 US 9901087 W US9901087 W US 9901087W WO 9936536 A9 WO9936536 A9 WO 9936536A9
Authority
WO
WIPO (PCT)
Prior art keywords
scramblase
cell
protein
cells
human
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1999/001087
Other languages
English (en)
Other versions
WO1999036536A2 (fr
WO1999036536A3 (fr
Inventor
Peter J Sims
Therese Wiedmer
Ji Zhao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Blood Center Research Foundation Inc
Original Assignee
Blood Center Research Foundation Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Blood Center Research Foundation Inc filed Critical Blood Center Research Foundation Inc
Priority to AU23262/99A priority Critical patent/AU2326299A/en
Priority to EP99903179A priority patent/EP1047779A2/fr
Publication of WO1999036536A2 publication Critical patent/WO1999036536A2/fr
Publication of WO1999036536A9 publication Critical patent/WO1999036536A9/fr
Publication of WO1999036536A3 publication Critical patent/WO1999036536A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • cell surface PS has a role in coagulation, programmed cell death and clearance by the reticuloendothelial system.
  • U.S. Serial No. 08/790,186 also describes regulation of the transmembrane distribution of PS, the role of calcium in the collapse of phospholipid asymmetry, and the role PL translocation in Scott Syndrome.
  • Transformed cancer cells exhibit the capacity to proliferate through unregulated mitotic division and to resist the normal cycle of senescence and programmed cell death characteristic of most normal untransformed cells. Additionally, malignant cancer cells in vivo exhibit the capacity to evade detection or injury by the body's immune defenses, including cellular killing by cytotoxic T-lymphocytes, humoral killing by antibody and complement, and removal by macrophages and other phagocytic cells of the reticuloendothelial system.
  • Fig . 7 graphs the Ca 2+ dependence of mutant human PL scramblase with amino acid substitutions in putative Ca 2+ binding site.
  • Fig. 8 is a Western blot analysis of PL scramblase protein and corresponding functional assay of PL scramblase activity in various human cell lines.
  • a defective form of the PL scramblase protein is expressed in the cell and that mutant PL scramblase inhibits the endogenous PL scramblase .
  • endogenous PL scramblase is inactivated by deacylating essential fatty acids from the protein that are required for normal PL scramblase function in the plasma membrane.
  • PL Scramblase Human PL scramblase amino acid residues in EF-hand Ca 2+ -binding motif at positions of Asp 273 , Asp 275 , Phe 277 , He 279 , Phe 281 and Asp 284 were mutated to Ala with oligonucleotide-directed mutagenesis by two rounds of PCR.
  • PL scramblase-pMAL-C2 was selected as template, and the first round of PCR was performed with pairs of a complementary oligonucleotide primer containing the point mutation plus a primer complementary to a site near the ATG initial codon or TAG stop codon.
  • PCR products were purified by Wizard kit.
  • Proteoliposomes reconstituted with erythrocyte PL scramblase exhibit accelerated transbilayer movement of fluorescent phospholipids in response to added Ca 2+ , similar to the observed effect of calcium on the endofacial surface of the red cell membrane (Q. Zhou, et al., supra , 1997; J.G. Stout, e_t al . , J ⁇ . Clin. Invest. 99:2232-2238, 1997; Basse, et al. , J. Biol. Chem. 271:17205-17210, 1996).
  • Fig. 8 depicts western blot analysis of PL scramblase in various human cell lines. Constitutive expression of PL scramblase was analyzed in the human cell lines indicated.
  • Upper Panel Results obtained by Western blotting with antibody specific for PL scramblase carboxyl terminal residues E306-W318 (see Materials & Methods) . Each lane contains the total protein extract of 1.5 x 10 6 cells.
  • Lower Panel Cumulative results of three separate experiments performed as follows: The cells indicated were washed and suspended at 37°C in the presence of 1.2 mM free Ca 2 ", and 2 ⁇ M A23187 was added.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention concerne une méthode d'accroissement de la viabilité des cellules ou des tissus mammifères, consistant à inhiber l'expression de la PL-scramblase native dans les cellules ou les tissus. Dans un autre mode de réalisation, l'invention concerne une méthode de réduction du potentiel métastatique et invasif ainsi que du potentiel de viabilité des cellules cancéreuses, des tissus cancéreux, ou des cellules infectées par virus, par l'augmentation de l'expression ou l'activité de la protéine PL-scramblase dans les cellules ou les tissus en question.
PCT/US1999/001087 1998-01-20 1999-01-19 Methodes et compositions permettant de modifier la sensibilite des tissus face aux lesions immunitaires, a la mort cellulaire programmee et a la clairance par le systeme reticulo-endothelial Ceased WO1999036536A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU23262/99A AU2326299A (en) 1998-01-20 1999-01-19 Methods and compositions to alter tissue susceptibility to immune injury, to programmed cell death, and to clearance by the reticuloendothelial system
EP99903179A EP1047779A2 (fr) 1998-01-20 1999-01-19 Methodes et compositions permettant de modifier la sensibilite des tissus face aux lesions immunitaires, a la mort cellulaire programmee et a la clairance par le systeme reticulo-endothelial

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7195098P 1998-01-20 1998-01-20
US60/071,950 1998-01-20

Publications (3)

Publication Number Publication Date
WO1999036536A2 WO1999036536A2 (fr) 1999-07-22
WO1999036536A9 true WO1999036536A9 (fr) 1999-11-04
WO1999036536A3 WO1999036536A3 (fr) 1999-12-09

Family

ID=22104619

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/001087 Ceased WO1999036536A2 (fr) 1998-01-20 1999-01-19 Methodes et compositions permettant de modifier la sensibilite des tissus face aux lesions immunitaires, a la mort cellulaire programmee et a la clairance par le systeme reticulo-endothelial

Country Status (3)

Country Link
EP (1) EP1047779A2 (fr)
AU (1) AU2326299A (fr)
WO (1) WO1999036536A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030139359A1 (en) * 2001-12-04 2003-07-24 Isis Pharmaceuticals Inc. Antisense modulation of phospholipid scramblase 3 expression
US20030044979A1 (en) * 2001-04-05 2003-03-06 Isis Pharmaceuticals Inc. Antisense modulation of phospholipid scramblase I expression
IL147812A0 (en) * 2001-03-16 2002-08-14 N S T Neurosurvival Technologi Method for targeting chemical compounds to cells and pharmaceutical compositions used therein

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6172210B1 (en) * 1996-04-02 2001-01-09 Blood Center Research Foundation DNA encoding phospholipid scramblase
US6204035B1 (en) * 1996-04-02 2001-03-20 The Blood Center Research Foundation Methods and compositions to alter the cell surface expression of phosphatidylserine and other clot-promoting plasma membrane phospholipids

Also Published As

Publication number Publication date
EP1047779A2 (fr) 2000-11-02
WO1999036536A2 (fr) 1999-07-22
WO1999036536A3 (fr) 1999-12-09
AU2326299A (en) 1999-08-02

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