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Inhibition of pacap signalling for the prevention and treatment of thrombocytopenia

a technology of thrombocytopenia and signalling inhibition, which is applied in the direction of growth factors/regulators, animal/human proteins, biochemistry apparatus and processes, etc., can solve the problems of mild to even severe bleeding problems, compromise the patency of blood vessels, morbidity and mortality in developed countries, etc., to prevent or treat thrombocytopenia and inhibit pacap transcription or translation

Inactive Publication Date: 2010-05-27
LIFE SCI RES PARTNERS VZW
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Congenital or acquired disorders interfering with one of the platelet functions can lead to mild to even severe bleeding problems.
Finally, stimulated platelets interact with each other during platelet aggregation and a platelet-rich thrombus is formed, which can compromise the patency of blood vessels.
Arterial and venous thrombosis and their complications including ischemic stroke, acute myocardial infarction and venous thromboembolism, represent the major cause of morbidity and mortality in developed countries.
Although extensive studies have also been performed on its function in the immune system, limited data are available concerning its function on haemostasis.

Method used

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  • Inhibition of pacap signalling for the prevention and treatment of thrombocytopenia
  • Inhibition of pacap signalling for the prevention and treatment of thrombocytopenia
  • Inhibition of pacap signalling for the prevention and treatment of thrombocytopenia

Examples

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example 1

Generation of Megakaryocyte-Specific PACAP Overexpressing Mice

[0087]The murine GPIIb promoter (extending from +23 to 508 relative to the initiation start site) was excised from the mGPIIb-pGL3 plasmid by digestion with KpnI and BamHI and inserted into the KpnI-BamHI-digested PACAP-pcDNA3.1 vector (Invitrogen) in front of the mouse PACAP gene (Denarier et al. (1993), Biochem. Biophys. Res. Commun. 195:1360-1364). The mouse PACAP gene was amplified from brain cDNA with primers mPACAP1R 5′-GTAGCCGCTCGAGGATCTGCTACAAGTATGC-3′ [SEQ ID NO: 3] and mPACAP4F 5′-GTTAGCCGAATTCAGTTCAAGGTCTGGCTAG-3′ [SEQ ID NO: 4], sequenced, and cloned into the EcoRI-XhoI site of the pcDNA3.1 vector. The 2.2-kilobase (kb) KpnIDraIII fragment (GPIIb-PACAP) was excised and purified for zygote injection. The GPIIb promoter has been successfully used to restrict transgene expression to the megakaryocytic cell lineage of mice (Tronick-Le Roux et al. (1995) J. Exp. Med. 181:2141-2151). Transgenic PACAP overexpressing ...

example 2

PACAP Overexpression in Patients

A: Patient Descriptions

[0088]FIG. 1 represents a family characterised by an unbalanced segregation of the reciprocal translocation t(18;20) (p21;p13), of which different members suffer from unexplained mental retardation. The propositus (VI:1) is a 23-year-old boy with a hypogonadotropic hypogonadism and is followed for epilepsy, severe mental retardation, hyperactive behaviour and hypotonia. He has an increased bleeding tendency and the Ivy bleeding time was markedly prolonged (>15 minutes) but coagulation studies are normal. Electron microscopy of his platelets is completely normal but he presented on different occasions with a moderate thrombocytopenia, as his platelet count is always about 70-90×103 platelets / μl. His karyotype shows a partial trisomy 18p and monosomy 20p. His brother (VI:2), father (V:2) and maternal grandmother (IV:6) are phenotypically normal, have no bleeding problems and have a normal karyotype. In contrast, his mother (V:3) a...

example 3

Influence of PACAP in Platelet Aggregation by Studies in Mice

[0097]Functional platelet studies from patient VI:1 show that increased levels of PACAP(1-38) in plasma result in increased basal cAMP levels and a platelet hypofunction. The role of PACAP(1-38) in platelet function was also studied in mice by subcutaneous injection of polyclonal or monoclonal anti-PACAP antibodies.

[0098]FVB mice were injected three times subcutaneously with 200 mg of an anti-PACAP or a control anti-b2-glycoprotein I polyclonal antibody or four times with 50 mg of an anti-PACAP (PP1A4) or an anti-RGS2 monoclonal antibody with an interval of 3 days between injections. At day 14 after the first injection, whole blood from the inferior vena cava of mice anesthetized by intraperitoneal injection of 60 mg / kg sodium pentobarbital was drawn into 20 μg / mL hirudin. A platelet count was performed on the venous blood sample using the Cell Dyne 1300 (Abbott). Blood was centrifuged at 100 g for 10 min, allowing separat...

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Abstract

The present invention discloses the use of inhibitors and / or antagonists of PACAP signalling for the manufacture of a medicament for the prevention or treatment of decreased blood platelet numbers (thrombocytopenia).

Description

[0001]The present application is a continuation of application Ser. No. 10 / 542,238, filed Jul. 15, 2005 (allowed), which is a U.S. national phase of PCT / EP2004 / 001209, filed Jan. 16, 2004, which claims benefit of GB application Nos. 0300934.7, 0307667.6, and 0310037.7, filed Jan. 16, 2003, Apr. 3, 2003 and Apr. 3, 2003, respectively.FIELD OF THE INVENTION[0002]This invention relates to compounds useful in the control of the primary haemostasis and the modulation of platelet number, as well as methods of use of these compounds.BACKGROUND OF THE INVENTION[0003]The initial response to interruption of continuity of a blood vessel is defined as primary haemostasis. Platelets play a major role in the pathophysiology of primary haemostasis. The clinical importance of platelets first became obvious when thrombocytopenic patients, who later on were diagnosed as having immune mediated thrombocytopenia (ITP), had thrombocytopenic purpura. Platelets participate in haemostasis by sealing vascula...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K31/7088A61K38/00A61P7/00A61K38/22C07K16/18
CPCA01K2217/05A01K2227/105C07K16/18A61K38/196A61K38/2073A61K38/2278A61K2300/00A61P7/00
Inventor FRESON, KATHLEENGEET, CHRIS VANHOYLAERTS, MARC
Owner LIFE SCI RES PARTNERS VZW
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