Prevention of tissue ischemia, related methods and compositions

Inventors

Isenberg, Jeffrey S.Roberts, David D.Frazier, William A.

Assignees

Washington University in St Louis WUSTLUS Department of Health and Human Services

Publication Number

US-8236313-B2

Publication Date

2012-08-07

Expiration Date

2027-10-05

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Abstract

Provided herein are compositions and methods for preventing, ameliorating, and/or reducing tissue ischemia and/or tissue damage due to ischemia, increasing blood vessel diameter, blood flow and tissue perfusion in the presence of vascular disease including peripheral vascular disease, atherosclerotic vascular disease, coronary artery disease, stroke and influencing other conditions, by suppressing CD47 and/or blocking TSP1 and/or CD47 activity or interaction. Influencing the interaction of CD47-TSP1 in blood vessels allows for control of blood vessel diameter and blood flow, and permits modification of blood pressure and cardiac function. Under conditions of decreased blood flow, for instance through injury or atherosclerosis, blocking TSP1-CD47 interaction allows blood vessels to dilate and increases blood flow, tissue perfusion and tissue survival. This in turn reduces or prevents tissue necrosis and death. The therapeutics identified herein allow for precise regulation of blood flow to tissues and organs which need it, while substantially avoiding systemic complications. Methods and compositions described herein can be used to increase tissue survival under conditions of trauma and surgery, as well as conditions of chronic vascular disease. Also disclosed are methods for the treatment of elderly subjects using agents that affect TSP1 and CD47 and thereby affect tissue perfusion. Additionally, provided herein are compositions and methods for influencing blood coagulation, allowing for controlled increased or decreased blood clotting. Additionally, provided herein are compositions and methods for decreasing blood flow, as in the case of cancer through mimicking the effects of TSP1 and CD47 on blood vessel diameter and blood flow.

Core Innovation

The invention provides compositions and methods for preventing, ameliorating, and reducing tissue ischemia and tissue damage due to ischemia, increasing blood vessel diameter, blood flow, and tissue perfusion in the presence of vascular diseases such as peripheral vascular disease, atherosclerotic vascular disease, coronary artery disease, stroke, and other conditions. This is accomplished by suppressing CD47 and/or blocking thrombospondin-1 (TSP1) and/or CD47 activity or their interaction, thereby influencing blood vessel diameter and blood flow, modifying blood pressure and cardiac function, and controlling tissue survival under ischemic conditions.

The problem being solved is the inadequate blood flow to tissues and organs caused by disruption of the nitric oxide (NO)-mediated relaxation of vascular smooth muscle cells, which is critical to regulating vessel diameter and tissue perfusion. This disruption leads to significant diseases, morbidity, and mortality, including peripheral vascular disease, ischemic heart disease, stroke, and diabetes, as well as tissue death and delayed wound healing during and after surgery. Existing treatments such as hyperbaric oxygen, thrombolytics, anti-inflammatory agents, and angiogenesis promoters have yielded limited success in restoring tissue perfusion and blood flow.

The inventors discovered that TSP1 blocks the effects of NO in the vascular system by acting through the cell receptor CD47 to prevent blood vessel dilation and increase blood flow. Blocking the TSP1-CD47 interaction or suppressing CD47 increases blood flow, tissue perfusion, and oxygenation, thereby enhancing tissue survival under both acute and chronic ischemic conditions, including surgery, tissue trauma, atherosclerosis, and chronic vascular pathology. Furthermore, TSP1-CD47 signaling influences platelet function and blood coagulation, providing the means to control blood clotting.

Claims Coverage

The patent contains multiple independent claims focused on methods of increasing tissue perfusion, treating ischemic conditions, and improving tissue survival by administering pharmaceutical compositions comprising an antibody to CD47 that inhibits the interaction of thrombospondin-1 (TSP-1) and CD47.

Use of an antibody to CD47 to inhibit thrombospondin-1/CD47 interaction

Administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody to CD47, wherein the antibody inhibits the interaction of thrombospondin-1 (TSP-1) and CD47, to increase tissue perfusion or treat ischemic conditions.

Humanized antibody targeting CD47

Using a humanized antibody to CD47 that inhibits TSP-1/CD47 interaction for the above therapeutic purposes.

Treatment of age-related and vascular diseases

Applying the antibody to subjects at risk or having diseases such as ischemia/reperfusion injury, myocardial infarction, stroke, cerebral ischemia, sickle cell anemia, pulmonary hypertension, hypertension, atherosclerosis, vasculopathy, ischemia secondary to diabetes, and peripheral vascular disease.

Use in elderly subjects and surgical procedures

Administering to human subjects of about 65 or more years of age or those undergoing surgeries including integument, soft tissue, composite tissue, skin graft, limb reattachment, organ transplant surgeries, to improve tissue perfusion and survival.

Combination therapies

Co-administering nitric oxide donors or precursors alongside the anti-CD47 antibody compositions to enhance therapeutic effects.

Use in donor organs to reduce ischemic injury

Administering CD47 antibody compositions to donor organs prior to transplantation to reduce ischemic and reperfusion injury.

The independent claims describe therapeutic methods of increasing tissue perfusion and treating ischemic conditions by administering antibodies to CD47 that inhibit its interaction with TSP-1. These methods are applicable to a range of diseases, age groups, surgical interventions, and organ transplantation, and include the use of humanized antibodies and combination treatments involving nitric oxide donors.

Stated Advantages

Precise regulation of blood flow to tissues and organs in need, substantially avoiding systemic complications.

Increased tissue survival under conditions of trauma, surgery, and chronic vascular disease.

Ability to treat elderly subjects by increasing tissue perfusion and improving vascular responses.

Potential to control blood coagulation by modulating platelet aggregation through TSP1-CD47 targeting.

Enhancement of wound healing and graft survival.

Use in treating a broad range of diseases including peripheral vascular disease, coronary artery disease, stroke, and diabetes.

Documented Applications

Treatment of ischemia and tissue damage due to ischemic injury, including acute ischemia from trauma or surgery and chronic vascular diseases such as atherosclerosis.

Increasing survival and blood flow in skin grafts, burns, and reconstructive surgeries including reattachment of severed body parts.

Improving organ transplant survival by administering agents that target TSP1-CD47.

Treatment and prevention of peripheral vascular diseases, coronary artery diseases, cerebral ischemia, and stroke.

Modulation of blood clotting by influencing platelet function via TSP1-CD47 signaling.

Increasing tissue perfusion and ameliorating vascular complications in elderly subjects and subjects with atherosclerotic vascular disease.

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