Protein Succination Detection for DMF Treatment Risk Assessment
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Solution Overview
Problem
Current methods lack an accurate way to monitor the impact of dimethyl fumarate (DMF) treatment on patients with multiple sclerosis (MS) to assess the risk of progressive multifocal leukoencephalopathy (PML) and lymphopenia, as existing guidelines are insufficient for determining when to discontinue treatment based on white blood cell counts.
Innovation Solution
Methods for determining the level of fumarate ester-derived protein modification, such as succination, in test samples, including hydrolyzing proteins or enzymatically digesting peripheral blood mononuclear cells (PBMCs), followed by mass spectrometry to quantify modified cysteines, allowing comparison to control levels to adjust treatment programs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If white blood cell count monitoring is used to assess DMF treatment risk, then treatment safety can be monitored, but the monitoring is insufficient to accurately determine when to discontinue treatment
Solution Approach 1:
The patent transitions from monitoring total white blood cell count to measuring the specific parameter of fumarate ester-derived protein modification levels. This parameter change enables more precise assessment of immune cell susceptibility to excessive modification, providing accurate guidance for treatment discontinuation decisions while maintaining treatment safety monitoring.
Solution Approach 2:
The patent introduces protein modification levels as an intermediary marker that mediates between DMF treatment exposure and clinical outcomes. By measuring the intermediate biomarker (fumarate ester-derived protein modification) rather than directly measuring treatment efficacy or adverse events, the method provides early warning capability for treatment discontinuation decisions.
2Productivity
If current white blood cell count guidelines are followed, then treatment can be continued, but the risk of PML and lymphopenia cannot be accurately assessed
Solution Approach 1:
The patent implements a feedback mechanism where protein modification levels are measured and used to adjust treatment decisions. The measured modification levels feed back into the treatment protocol, enabling dynamic adjustment of treatment continuity based on individual patient risk profiles, thus resolving the contradiction between maintaining treatment and ensuring safety.
Solution Approach 2:
The patent performs preliminary measurement of protein modification levels before making treatment discontinuation decisions. By assessing the degree of protein modification in advance, clinicians can predict future risk of PML and lymphopenia, enabling proactive treatment adjustment rather than reactive response to adverse events.
3Measurement precision
If protein modification levels are measured to assess immune cell susceptibility, then treatment decisions can be optimized, but the measurement complexity increases
Solution Approach 1:
The patent extracts the specific information needed (fumarate ester-derived protein modification levels) from the complex biological system. By focusing measurement on this specific modified protein marker rather than attempting to measure all possible immune cell parameters, the method achieves high assessment accuracy while keeping the measurement procedure manageable through targeted analysis.
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
Provides a more accurate measure of immune cell susceptibility to excessive fumarate ester modification, enabling clinicians to modify or discontinue DMF treatment to prevent PML and lymphopenia, thereby improving patient safety and treatment efficacy.
Implementation Method 1
followed by mass spectrometry to quantify modified cysteines
Implementation Method 2
including hydrolyzing proteins or enzymatically digesting peripheral blood mononuclear cells (PBMCs)
Implementation Method 3
enzymatically digesting peripheral blood mononuclear cells (PBMCs)
Data Source
AI summary
Examination of a test sample to determine the presence or quantity of succination of proteins is described. Examination can be via protein hydrolysis in total succination determination or via enzymatic digestion of isolated proteins and determination of the presence or quantity of modified peptides. The methods can be utilized for determination of excessive succination of lymph system proteins, which can be utilized in prevention or early detection of lymphopenia. Methods can be utilized for test samples of subjects under treatment with dimethyl fumarate suffering from multiple sclerosis. Methods can be utilized as a determination that treatment of the subject with DMF should be slowed or stopped.