Proteolytic uPAR D2D3 Removal for Diabetes and Kidney Disease
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for chronic kidney diseases and diabetes, particularly diabetic nephropathy, do not adequately address the role of the C-terminal uPAR protein, D2D3, which contributes to kidney disease and insulin-dependent diabetes by impairing insulin release and podocyte injury, and there is a lack of therapeutic targets for these conditions.
Innovation Solution
The development of methods to measure D2D3 protein levels in biological samples and administer agents that antagonize or remove D2D3 from circulation, such as antibodies or extracorporeal processes like plasmapheresis, to treat chronic kidney disease and insulin-dependent diabetes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for chronic kidney disease and diabetes are used, then existing symptoms are managed, but the role of D2D3 protein is not addressed and therapeutic effectiveness is limited
Solution Approach 1:
The invention segments the uPAR protein into functional domains (D1, D2, D3) and identifies D2D3 as a distinct proteolytic fragment with specific pathogenic activity. By targeting this specific segment (D2D3) rather than the entire uPAR protein, the therapy achieves greater specificity and effectiveness against diabetic nephropathy and insulin-dependent diabetes.
Solution Approach 2:
The invention extracts and isolates the D2D3 fragment from the full uPAR protein sequence, identifying it as the specific pathogenic component. This extraction allows for targeted therapeutic intervention against D2D3 alone, separating its harmful effects from the potentially beneficial functions of other uPAR domains.
2Measurement precision
If D2D3 protein levels are increased for measurement accuracy, then diagnostic precision improves, but the complexity of detection methods increases
Solution Approach 1:
The invention develops detection methods that specifically target the D2D3 fragment with localized specificity, using antibodies or assay components that recognize unique epitopes on D2D3. This local quality approach allows precise measurement of D2D3 levels without requiring complex analyses of the entire uPAR protein or other protein components.
3Reliability
If agents are administered to antagonize or remove D2D3, then therapeutic effect is achieved, but the complexity of treatment protocols increases
Solution Approach 1:
The invention uses antibodies or other binding agents as intermediaries that specifically recognize and bind to D2D3 protein. These intermediary molecules facilitate the removal or neutralization of D2D3 through mechanisms such as plasmapheresis or immune complex formation, simplifying the overall treatment approach by providing a direct target for intervention.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Blocking D2D3 protein ameliorates insulin-dependent diabetes and kidney diseases by restoring β-cell function and reducing kidney damage, providing a dual therapeutic approach for these conditions.
Implementation Method 1
administering a therapeutically effective amount of an agent that antagonizes D2D3 and/or removes D2D3 from circulation of the subject. In some embodiments, the agent can be an antibody or antibody fragment. In embodiments, the agent comprises an anti-D2D3 antibody or antigen-binding fragment thereof that specifically binds to a D2D3 protein.
Implementation Method 2
suPAR is generated by proteolytic shedding of the membrane-bound uPAR from the surface of various cells of the innate immune system such as macrophages, immature myeloid cells, and neutrophils.
Implementation Method 3
uPAR proteolysis generates two additional circulating forms: an N-terminal DI fragment and a C-terminal D2D3 protein
Implementation Method 4
uPAR/suPAR causes CKD by activating αvβ3 integrin on glomerular podocytes, leading to foot process (FP) effacement and proteinuria.
Data Source
AI summary
The current invention discloses methods for treating diseases characterized by elevated levels of the urokinase plasminogen activator receptor (uPAR) protein D2D3 wherein the disease is one or more of chronic kidney disease, insulin-dependent diabetes, or diabetic neuropathy. In addition, the invention provides methods for restoring pancreatic β-cell number and function in the pancreas of a subject diagnosed with insulin-dependent diabetes wherein the insulin-dependent diabetes is characterized by the presence of detectable levels of D2D3 Specifically, the methods comprise administration of a therapeutically effective amount of an agent that antagonizes or removes D2D3 from the circulation of the subject wherein the agent comprises an anti-D2D3 antibody or antigen binding fragment thereof that specifically binds to a D2D3 protein. Alternatively, the methods comprise removing the D2D3 protein from the circulation of the subject by an extracorporeal procedure.