Prevention of tissue ischemia and related methods
Inventors
Isenberg, Jeffrey S. • Roberts, David D. • Frazier, William A.
Assignees
United States, REPRESENTED BY SECRETARY Depar Tment Of Health And Human Services AS • Washington University in St Louis WUSTL • US Department of Health and Human Services
Publication Number
US-11254735-B2
Publication Date
2022-02-22
Expiration Date
2027-10-05
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Abstract
Provided herein are compositions 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.
Core Innovation
This invention provides compositions and methods for preventing, ameliorating, and reducing tissue ischemia and/or tissue damage due to ischemia by modulating the interaction between thrombospondin-1 (TSP1) and its receptor CD47. The discovery that TSP1 blocks the effects of nitric oxide (NO) in blood vessels, preventing vasodilation and increasing blood flow, leads to methods to manipulate blood vessel diameter, blood flow, and tissue perfusion by suppressing CD47 or blocking TSP1-CD47 activity or interaction.
The problem being solved is the disruption of adequate blood flow to tissues and organs, which leads to diseases such as peripheral vascular disease, ischemic heart disease, stroke, diabetes, and problems in wound healing during and after surgery. Existing treatments addressing restoration of tissue perfusion and blood flow, such as hyperbaric oxygen and thrombolytics, have had limited success.
The core innovation reveals that blocking the TSP1-CD47 interaction enhances NO signaling, leading to increased blood vessel dilation, blood flow, and tissue survival under both acute and chronic ischemic conditions. Therapeutic agents such as anti-CD47 or anti-TSP1 antibodies, peptides, and morpholinos can be used to inhibit this interaction, thus increasing tissue survival, improving skin graft survival, modulating blood clotting, and preventing ischemic tissue necrosis. The invention also includes use in elderly subjects with vascular disease and other ischemia-related conditions.
Claims Coverage
The patent contains multiple independent claims focusing on isolated peptides that specifically bind CD47 and methods related to their use in promoting clotting.
Peptide binding to CD47 with specified sequence motif
An isolated or synthetic peptide of 8 to 10 amino acids length specifically binding CD47, comprising the sequence R1—X1—X2—X3-Lys-X4—X5—X6—X7—X8-Arg-X9—R2 with defined residues and variable positions as detailed in the claim, including certain preferred amino acids and sequences.
Functional and structural peptide variants and pharmaceutical compositions
Peptides of claim 1 that may be modified by detectable labels or groups improving stability or bioavailability, or pharmaceutical compositions comprising such peptides or their encoding nucleic acids formulated with pharmaceutically acceptable carriers, for example for topical application or wound dressing.
Methods of treating hemorrhage using peptides or compositions
Methods for treating hemorrhage or controlling bleeding in tissues or subjects by contacting with the specified CD47-binding peptides or pharmaceutical compositions thereof, applicable to trauma, surgery, or bleeding disorders.
The claims focus on CD47-binding peptides of specified length and sequence features, modified forms and pharmaceutical compositions thereof, and therapeutic methods for treating bleeding disorders or controlling hemorrhage. The invention covers both the molecular entities and their clinical applications.
Stated Advantages
Compositions and methods based on blocking TSP1 or CD47 increase blood vessel diameter, blood flow, and tissue perfusion in ischemic conditions.
Targeting the TSP1-CD47 interaction dramatically increases tissue survival and viability following ischemic injury including surgery, burns, and vascular diseases.
Therapeutic use of antibodies, peptides, and morpholinos enables selective enhancement of blood flow and improved healing, especially in aged subjects with vascular pathology.
Agents mimicking TSP1 actions through CD47 help enhance blood clotting and prevent bleeding, useful in trauma, surgery, and congenital bleeding disorders.
New therapeutic approaches based on TSP1-CD47 modulation can prevent tissue necrosis and improve outcomes in ischemic disease and tissue transplantation.
Documented Applications
Treatment of tissue ischemia and reduction of ischemic tissue damage and necrosis in conditions such as peripheral vascular disease, atherosclerotic vascular disease, coronary artery disease, stroke, diabetes, and wound healing after surgery or trauma.
Increasing skin graft survival, healing of burn wounds, and survival of composite tissue flaps by modulation of TSP1-CD47 activity.
Use in elderly subjects to improve blood flow and tissue survival under acute and chronic vascular pathologies including age-related vasculopathy and atherosclerosis.
Modulation of platelet function and blood clotting, including enhancement of clotting in bleeding disorders and control of thrombosis to minimize complications in stroke and coronary artery disease.
Application of therapeutic agents locally or systemically, including via implantable devices such as vascular stents for sustained release, topical applications for wounds and burns, and possibly in organ transplantation and reattachment of severed extremities.
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