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Nucleotide phosphate dissipation as a treatment for vascular disorders

Inactive Publication Date: 2009-05-21
RGT UNIV OF MICHIGAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]The present invention is related to methods of treating or preventing immunoinflammatory, vascular, thrombotic or ischemic disorders in a subject by administering an agent which dissipates nucleotide phosphates (nucleotide mono, di, or triphosphates), as well as an agent which may act by increasing adenosine levels. Protective actions may be conferred by inhibiting macrophage infiltration into a site, promoting vasodilation, limiting apoptosis, reducing edema, or interfering with coagulation, or other mechanisms which restore vascular homeostasis. The subject invention comprises administering to the subject an effective amount of CD73 or nucleotidase, a fragment a mutant, or a modified form thereof. The present invention also provides a method for inhibiting macrophage infiltration into a site in a subject which comprises administering to the subject a compound capable of increasing endogenous CD73 levels. Furthermore, this invention reveals that cyclic AMP or other second messenger stimulating pathways (such as cGMP analogues, nitric oxide or its donors or carbon monoxide or its donors, or phosphodiesterase inhibitors) which raise nucleotidase levels can be protective against ischemic, inflammatory, vascular, or atherosclerotic disorders which may include any of the conditions listed above.

Problems solved by technology

In the settings in which these ectonucleotidases are insufficiently active, inflammation, thrombosis, edema, and apoptosis can result.
By inhibiting the infiltration of macrophages and other specific leukocyte populations into ischemic areas or inflammatory sites, damage to tissue in these areas or sites can be limited.

Method used

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  • Nucleotide phosphate dissipation as a treatment for vascular disorders
  • Nucleotide phosphate dissipation as a treatment for vascular disorders
  • Nucleotide phosphate dissipation as a treatment for vascular disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Lung Transplant

[0173]Acute rejection after lung transplantation is a main risk factor for the development of bronchiolitis obliterans (BO) syndrome and is characterized by a perivascular and bronchiolar leukocyte infiltration. The specific mechanisms by which these leukocytes are recruited have not been elucidated. CD73 catalyzes the extracellular conversion of 5′-AMP to adenosine, which has anti-inflammatory actions, a contributory role for CD73 in BO development was examined using murine tracheal transplantation models.

Mice

[0174]Male mice aged between 8 and 12 weeks old were used in these experiments. C57BL / 6 (H-2b) mice and B10.A (H-2a) mice were purchased from Jackson Laboratories. Isogeneic tracheal transplants were performed using C57BL / 6J mice as both recipients and donors. Allogeneic (B10.A) tracheal grafts from donor mice were transplanted into wild-type (C57BL / 6) or CD73− / − recipient mice. To specifically determine the role of epithelial- versus leukocyte-derived CD73− / −, ...

example 2

Heart Transplant Ecto-5′ Nucleotidase (CD73)-Mediated Adenosine Generation and Signaling in Murine Cardiac Allograft Vasculopathy

[0190]Experiments herein examine a role for CD73 and specific adenosine receptor subtypes in modulating leukocyte trafficking and ultimately, rejection and CAV following cardiac allotransplantation.

Materials and Methods

[0191]Animals. CD73-deficient mice (CD73− / −) of C57BL / 6 (H-2b) background, are described previously9. CD73+ / + littermates were used as the wild-type control. B10A (H-2a) and CBA / J (H-2k) mice were purchased from The Jackson Laboratories (Bar Harbor, Me.).

[0192]Experimental groups. Completely allomismatched murine heterotopic cardiac transplantation was performed for the present study, as previously described in detail by us13. Two groups (n=6 in each group) were used to study donor sources of CD73 (CD73+ / + or CD73− / − donors into B10A recipients) and another two groups (n=6 in each group) were used to study recipient sources (B10A donors into...

example 3

Cerebrovascular Ischemia; Endothelial Ecto-5′ Nucleotidase (CD73) Regulation of Leukocyte Trafficking in the Ischemic Brain

Methods

[0204]All reagents, unless stated otherwise, were obtained from Sigma (St. Louis, Mo., USA).

[0205]CD73-deficient mice (CD73− / −), were as described above. Wild-type C57B1 / 6J mice were purchased from Jackson Laboratory (Bar Harbor, Me., USA) and used as controls.

Photothrombotic Model of Cerebral Ischemia

[0206]Permanent occlusion of middle cerebral artery (MCAO) was induced using a technique wherein a laser light was applied on the middle cerebral artery after the mouse had received an intravenous injection of a photoreactive material.

[0207]Ten week old male mice were anesthetized with 2.5 mg intraperitoneal ketamine and 0.25 mg xylazine (Phoenix Pharmaceutical). Body temperature was at 37° C. maintained during surgery and for 45 minutes thereafter using a temperature controlled circulating liquid heating pad. After opening an oval bony window, 2-3 mm in dia...

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Abstract

The present invention provides a method of treating or preventing immunoinflammatory, vascular, thrombotic or ischemic disorders in a subject, the method comprises administering to the subject an agent which dissipates nucleotide phosphates or generates a product which stimulates adenosine receptors. The present invention also provides a method of treating or preventing immunoinflammatory, thrombotic or ischemic disorders in a subject by inhibiting leukocyte infiltration into a site which comprises administering to the subject an effective amount a described agent. Agents described for use in the methods of the invention include CD73, a fragment a mutant, or a modified form thereof.

Description

[0001]This application claims the benefit of priority of U.S. provisional applications 60 / 983,649, filed Oct. 30, 2007, and 60 / 985,106, filed Nov. 2, 2007.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]The invention described herein was made in the course of work done under Grant number HL086676 from the National Institute of Health. Therefore, the United States Government may have certain rights in this invention.SEQUENCE LISTING[0003]The present application is being filed with an electronic format Sequence Listing submitted herewith. The listing is provided as a file entitled SQ0378.txt, created Oct. 30, 2008, and is 19 Kb in size. The entire contents of this electronic format Sequence Listing is hereby incorporated by reference.FIELD OF THE INVENTION[0004]The invention relates to methods of treating or preventing immunoinflammatory, vascular, thrombotic or ischemic disorders by administering one or more agents which dissipate nucleoside or nucleotide phospha...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K38/43
CPCC12Y301/03005A61K38/465
Inventor PINSKY, DAVID J.PETROVIC-DJERGOVIC, DANICA
Owner RGT UNIV OF MICHIGAN
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