Prevention of tissue ischemia and related methods
Inventors
Isenberg, Jeffrey S. • Roberts, David D.
Assignees
US Department of Health and Human Services
Publication Number
US-10370439-B2
Publication Date
2019-08-06
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
Provided are compositions and methods to prevent, ameliorate, and reduce tissue ischemia and damage by suppressing CD47 and/or blocking thrombospondin-1 (TSP1) and/or CD47 activity or their interaction. Influencing the CD47-TSP1 interaction in blood vessels allows control over blood vessel diameter, blood flow, and tissue perfusion. Under conditions of decreased blood flow, such as injury or atherosclerosis, blocking TSP1-CD47 interaction permits vessel dilation, increased blood flow, tissue perfusion, and survival.
The invention addresses the clinical problem that inadequate blood flow at the organ and tissue levels leads to conditions including peripheral vascular disease, ischemic heart disease, stroke, and diabetes. Existing treatments like hyperbaric oxygen and anti-inflammatory agents have had limited success in treating ischemia and associated tissue damage. The inventors discovered that TSP1 blocks nitric oxide (NO)-mediated vasodilation and blood flow increases via the receptor CD47, thereby limiting tissue perfusion. Genetic or therapeutic blockade of TSP1 or CD47 markedly improves blood flow and tissue oxygenation under ischemic conditions, resulting in enhanced tissue survival.
Therapeutic compounds that block TSP1/CD47 interaction include monoclonal antibodies, peptides derived from TSP1 or CD47, antisense oligonucleotides, and morpholinos targeting CD47 or TSP1. Targeting this pathway allows prevention or reversal of tissue ischemia and damage in conditions involving vascular disease, such as peripheral vascular disease, atherosclerosis, stroke, and coronary artery disease. It also modulates blood clotting through effects on platelet function. Ultimately, this discovery offers novel compositions and methods that regulate NO signaling to improve tissue survival, control blood vessel responses, and treat acute and chronic ischemic conditions including those related to aging.
Claims Coverage
The patent claims center on methods for increasing tissue perfusion or treating ischemia by administering humanized antibodies specific for thrombospondin-1 (TSP1).
Use of humanized anti-TSP1 antibodies for increasing tissue perfusion and treating ischemia
Methods of selecting subjects in need of increased tissue perfusion or ischemic treatment and administering therapeutically effective amounts of pharmaceutical compositions comprising humanized antibodies to TSP1, specifically humanized versions of antibody A6.1 or antibody C6.7.
Treatment of various ischemic conditions and surgeries with humanized anti-TSP1 antibodies
Application of humanized anti-TSP1 antibodies to subjects having or at risk of ischemia/reperfusion injury, myocardial infarction, stroke, cerebral ischemia, sickle cell anemia, pulmonary hypertension, hypertension, atherosclerosis, vasculopathy, diabetes-associated ischemia, peripheral vascular disease, integument, soft tissue, composite tissue surgeries, skin graft surgeries, reattachment surgeries, and organ transplant surgeries.
Combination therapies involving humanized anti-TSP1 antibodies and NO-related agents
Methods further comprising co-administration of nitric oxide donors or precursors, nitrovasodilators, activators of soluble guanylyl cyclase, or cGMP phosphodiesterase inhibitors to enhance therapeutic outcomes.
Use of humanized anti-TSP1 antibodies for donor organ treatment
Administration of humanized anti-TSP1 antibodies to donor organs prior to transplantation to improve outcomes, optionally in combination with nitric oxide-related agents.
The claims cover therapeutic uses of humanized antibodies against TSP1, particularly humanized versions of A6.1 and C6.7, for increasing tissue perfusion, treating ischemic injuries and conditions, enhancing survival in various surgical and transplant scenarios, and optionally combined with NO donor or related agents, thereby modulating the TSP1-CD47 pathway for vascular and tissue health.
Stated Advantages
The therapeutic agents targeting TSP1 and CD47 dramatically increase blood flow and tissue survival under ischemic conditions.
They allow selective alteration in regional blood flow to vital organs, avoiding systemic side effects.
Blocking TSP1 or CD47 enhances skin graft survival, improves wound healing, and increases tissue perfusion even in aged subjects with vascular disease.
Agents can be used to modulate blood clotting, providing control over platelet aggregation for treating bleeding or thrombotic disorders.
Targeting TSP1-CD47 interaction provides a novel means to harness the benefits of nitric oxide signaling throughout the body.
Documented Applications
Treatment of tissue ischemia and improving tissue survival following injury, surgery, burn wounds, skin grafting, and peripheral vascular disease.
Use in conditions involving decreased blood flow including atherosclerosis, coronary artery disease, stroke, diabetes, and vasculopathies associated with aging.
Promotion of blood flow and tissue perfusion in grafts, organ transplantation, reattachment of severed body parts, and wound healing.
Modulation of platelet function and blood clotting to manage bleeding disorders and thrombotic complications.
Increasing tissue perfusion and blood flow in elderly subjects to ameliorate age-related vascular insufficiencies and improve healing.
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