Mutated β-Glucocerebrosidase With Disulfide-Bond Stabilization
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current enzyme replacement therapies for Gaucher disease are costly and require frequent intravenous injections due to the instability and limited delivery of β-Glucocerebrosidase (GCase) enzymes to target organs, leading to a high treatment burden for patients.
Innovation Solution
Development of modified GCase polypeptides with specific amino acid substitutions, such as at positions 351 and 380, which enhance stability and activity, allowing for increased half-life and reduced immunogenicity, enabling delivery via gene therapy to target organs and potentially reducing the frequency of injections.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If enzyme replacement therapy is administered frequently via intravenous injection, then therapeutic effect is maintained, but treatment burden and cost increase significantly
Solution Approach 1:
The patent introduces specific amino acid substitutions (W351C and A380C) in the GCase enzyme to change its biochemical parameters, specifically enhancing stability and half-life. This allows the enzyme to maintain therapeutic levels for longer periods, reducing injection frequency from every other week to potentially monthly or less frequent administrations
2Reliability
If GCase enzyme is delivered to target organs, then therapeutic effect is achieved, but enzyme stability and delivery efficiency are limited
Solution Approach 1:
The patent modifies the enzyme's amino acid sequence by substituting tryptophan at position 351 with cysteine and alanine at position 380 with cysteine. These parameter changes at the molecular level enhance the enzyme's structural stability and resistance to degradation, improving its half-life and delivery efficiency to target organs
Solution Approach 2:
The patent creates a modified composite enzyme structure by introducing disulfide bonds through cysteine substitutions. These structural modifications create a more stable composite protein structure that resists denaturation and degradation, enhancing overall enzyme stability without compromising catalytic activity
3Reliability
If higher doses of GCase are administered, then therapeutic effect is enhanced, but cost and potential immunogenicity increase
Solution Approach 1:
The patent optimizes the enzyme's amino acid parameters to achieve higher stability and longer half-life. This allows lower doses to achieve the same area-under-the-curve (AUC) exposure, reducing the 100,000-fold dose variability seen in current therapies and minimizing immunogenicity risks associated with high-dose administrations
Data Source
Figure 1
Figure 2A~2B
Figure 3A~3B
AI summary
The present invention relates to a modified β-Glucocerebrosidase (GCase) polypeptide and a polynucleotide comprising a modified glucocerebrosidase (GBA) nucleotide sequence. The invention further relates to a viral particle comprising a recombinant genome comprising the polynucleotide of the invention, and a composition comprising the modified GCase polypeptide, polynucleotide, or viral particle of the invention. The invention also relates to methods of using, and uses of, the modified GCase polypeptide, polynucleotide, viral particle and/or composition of the invention. The invention further relates to the modified GCase polypeptide, polynucleotide, viral particle, or composition of the invention for use in a method of treatment, or use in the manufacture of a medicament for use in a method of treatment.