High-Concentration Alpha-Glucosidase Compositions for Aggregation Control
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Solution Overview
Problem
Current enzyme replacement therapies for Pompe disease, such as recombinant α-glucosidase, face challenges with enzyme instability, aggregation, and inefficient tissue uptake, particularly at high concentrations, which limits their therapeutic efficacy.
Innovation Solution
Administering recombinant human α-glucosidase (rhGAA) in combination with an Active Site-Specific Chaperone (ASSC), like 1-deoxynojirimycin, at high concentrations to stabilize the enzyme's conformation and reduce aggregation, facilitating effective subcutaneous delivery and increased tissue uptake.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If recombinant α-glucosidase is administered at high concentrations, then therapeutic efficacy is improved, but enzyme aggregation increases
Solution Approach 1:
The patent introduces active site-specific chaperones (ASSCs) as intermediary molecules that bind to the active site of recombinant α-glucosidase. These chaperones act as protective intermediaries that prevent aggregation of the enzyme at high concentrations while maintaining its catalytic activity, thereby enabling high-dose therapy without the harmful aggregation effects
2Quantity of substance
If recombinant α-glucosidase is administered at high concentrations, then therapeutic efficacy is improved, but enzyme instability increases
Solution Approach 1:
Active site-specific chaperones serve as stabilizing intermediaries that bind to the enzyme's active site and maintain its proper conformation. This intermediary binding prevents denaturation and degradation that normally occur at high concentrations, thereby improving enzyme reliability and stability in the therapeutic formulation
3Productivity
If enzyme replacement therapy is administered, then glycogen metabolism is improved, but tissue uptake efficiency is limited
Solution Approach 1:
The active site-specific chaperones act as mediators that facilitate the interaction between recombinant α-glucosidase and target tissues. By binding to the active site, these chaperones may enhance the enzyme's recognition and uptake by lysosomal pathways in affected tissues, thereby improving delivery efficiency while maintaining metabolic function
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 combination of rhGAA with ASSC enhances enzyme stability and tissue uptake, maintaining high concentrations without aggregation, leading to improved therapeutic outcomes for Pompe disease.
Implementation Method 1
an Active Site-Sspecific Chaperone (ASSC), such as 1-deoxynojirimycin, to stabilize the enzyme's conformation and reduce aggregation
Data Source
AI summary
The present application provides for compositions comprising high concentrations of acid α-glucosidase in combination with an active site-specific chaperone for the acid α-glucosidase, and methods for treating Pompe disease in a subject in need thereof, that includes a method of administering to the subject such compositions. The present application also provides methods for increasing the in vitro and in vivo stability of an acid α-glucosidase enzyme formulation.