TSP1-CD47 Interaction Blockade for Ischemic Tissue Perfusion
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Solution Overview
Problem
Current treatments for acute and chronic ischemia, such as in soft tissue flaps or skin grafts, have limited success in restoring tissue perfusion and blood flow, leading to tissue damage and wound healing issues during and after surgery, and are ineffective in managing diseases like atherosclerotic vascular disease and diabetes.
Innovation Solution
The discovery that thrombospondin-1 (TSP1) blocks nitric oxide (NO) effects in the vascular system by interacting with the CD47 receptor, and using reagents like monoclonal antibodies, peptides, or antisense oligonucleotides to block this interaction increases blood flow and tissue oxygenation, thereby improving tissue survival and blood vessel function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If thrombospondin-1 (TSP1) blocks nitric oxide (NO) effects in the vascular system, then blood vessel contraction is maintained and blood flow is restricted, but tissue ischemia and oxygenation are worsened
Solution Approach 1:
The patent extracts and neutralizes the harmful blocking effect of TSP1 on NO signaling. By administering NO donors or TSP1 inhibitors, the invention removes the pathological interference TSP1 creates between NO and vascular smooth muscle cells, thereby restoring proper vasodilation and blood flow without requiring removal of TSP1 itself
Solution Approach 2:
The patent introduces intermediary substances (NO donors, TSP1 inhibitors, or combination therapies) that mediate between the conflicting elements of TSP1 blocking and NO signaling. These intermediaries restore the NO-cGMP pathway function, enabling vasodilation and improved tissue perfusion despite the presence of TSP1
2Reliability
If current treatments like hyperbaric oxygen and thrombolytics are used, then some improvement in tissue perfusion is achieved, but success rates remain limited and many conditions remain ineffective
Solution Approach 1:
The patent creates a universal therapeutic approach that addresses multiple ischemic conditions through a common mechanism. By targeting the fundamental TSP1-NO interaction pathway that is disrupted across various conditions (atherosclerosis, diabetes, peripheral vascular disease, acute ischemia), the invention provides a versatile treatment that can be adapted to different clinical scenarios while maintaining reliable efficacy
Solution Approach 2:
The patent changes the therapeutic parameter from addressing downstream consequences of ischemia to correcting the upstream molecular interaction defect. By modifying the biochemical parameters of NO signaling and TSP1 activity, the treatment achieves reliable improvement in tissue perfusion across diverse conditions that previously responded poorly to conventional therapies
Data Source
AI summary
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.