Pharmacological Chaperone Dosing Cycles for Lysosomal Enzyme Trafficking
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Solution Overview
Problem
Current treatments for lysosomal storage diseases, such as Gaucher and Fabry diseases, are limited, and there is a need for effective dosing regimens of pharmacological chaperones to stabilize mutant enzymes and increase their trafficking to lysosomes, thereby enhancing enzyme activity and reducing substrate accumulation.
Innovation Solution
Specific dosing regimens for pharmacological chaperones like isofagomine and 1-deoxygalactonojirimycin are developed, involving varying administration schedules to optimize enzyme stability and activity, including daily and maintenance doses, with optional washout periods, to enhance enzyme trafficking and reduce substrate accumulation in lysosomes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If pharmacological chaperones are administered continuously at high doses, then enzyme stability and trafficking are improved, but enzyme inhibition and substrate accumulation worsen
Solution Approach 1:
The patent implements periodic dosing regimens with alternating treatment and washout periods. During treatment periods, pharmacological chaperones are administered to stabilize and traffic enzymes to lysosomes. During subsequent washout periods, the drug is discontinued to allow enzyme inhibition to subside and accumulated enzymes to exert therapeutic effect. This periodic approach resolves the contradiction by temporally separating the stabilization function from the inhibition side effect.
Solution Approach 2:
The patent applies preliminary action by administering pharmacological chaperones during a treatment phase before the washout phase. This preliminary administration allows sufficient time for enzyme stabilization, trafficking to lysosomes, and accumulation of active enzyme in the target organelle. The enzyme is prepared and positioned in advance before the drug is removed, ensuring therapeutic benefit is established before inhibition becomes problematic.
2Stability of the object's composition
If pharmacological chaperones are administered to stabilize mutant enzymes, then enzyme trafficking to lysosomes is improved, but the complexity of dosing regimens increases
Solution Approach 1:
The patent segments the dosing regimen into distinct treatment periods and washout periods. Each treatment period consists of specific dosing schedules (e.g., daily, every other day, or weekly dosing), followed by defined washout periods where no drug is administered. This segmentation transforms a potentially complex continuous dosing strategy into manageable discrete phases, making the regimen easier to implement and monitor while achieving the dual goals of enzyme stabilization and inhibition reduction.
3Productivity
If pharmacological chaperones are used to increase enzyme activity, then substrate accumulation is reduced, but the risk of adverse effects from prolonged drug exposure increases
Solution Approach 1:
The patent employs periodic action by structuring treatment as alternating cycles of drug administration and washout periods. During treatment periods, enzyme activity is enhanced through pharmacological chaperone administration, leading to substrate reduction. During washout periods, drug exposure ceases, allowing adverse effects to diminish while the accumulated enzyme continues to function therapeutically. This periodic pattern maintains productivity while minimizing harmful effects.
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
The dosing regimens increase enzyme activity and reduce substrate accumulation, leading to improved clinical outcomes in lysosomal storage diseases, as evidenced by increased enzyme levels, reduced GL-3 accumulation, and decreased left ventricular mass index, among other surrogate markers.
Implementation Method 1
small molecule competitive inhibitors as pharmacological chaperones for the treatment of lysosomal storage diseases... binding of small molecule inhibitors of enzymes associated with LSDs can increase the stability of both mutant enzyme and the corresponding wild-type enzyme
Implementation Method 2
small molecule competitive inhibitors as pharmacological chaperones... small molecule derivatives of glucose and galactose, which are specific, selective competitive inhibitors for several target lysosomal enzymes, effectively increased the stability of the enzymes in cells in vitro and, thus, increased trafficking of the enzymes to the lysosome
Data Source
AI summary
The present invention provides dosing regimens for administering pharmacological chaperones to a subject in need thereof. The dosing regimens can be used to treat disorders caused by improper protein misfolding, such as lysosomal storage disorders.