Codon-Optimized GBA Polynucleotides for Stable GCase Expression
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Solution Overview
Problem
Current enzyme replacement therapies for Gaucher disease require frequent and lifelong intravenous injections, resulting in a significant treatment burden for patients.
Innovation Solution
A gene therapy approach involving the administration of viral particles carrying a codon-optimised GBA nucleotide sequence encoding β-Glucocerebrosidase (GCase), which enhances GCase expression and activity in the liver and other tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If enzyme replacement therapy is used to treat Gaucher disease, then GCase activity is restored in patients, but treatment burden and cost increase significantly due to frequent lifelong injections
Solution Approach 1:
The patent applies preliminary action by delivering a functional GBA gene copy to patient cells in advance, enabling the cells to produce GCase endogenously. This upfront genetic modification eliminates the need for repeated enzyme administrations, as the corrected cells continuously produce the missing enzyme throughout the patient's life.
Solution Approach 2:
The invention implements self-service by enabling patient's own cells to produce the therapeutic enzyme through gene transfer. The modified cells autonomously synthesize GCase without external intervention, allowing the body's cellular machinery to serve its own therapeutic needs and eliminate dependence on external enzyme replacement.
2Reliability
If wild type GBA nucleotide sequence is used for gene therapy, then GCase expression is achieved, but expression levels are insufficient for effective treatment
Solution Approach 1:
The patent applies parameter changes by modifying the nucleotide sequence parameters of the GBA gene, specifically optimizing codon usage to match human cellular preferences. This codon optimization changes the genetic code parameters without altering the amino acid sequence, thereby enhancing translation efficiency and increasing GCase protein expression levels to therapeutically effective amounts.
3Reliability
If frequent intravenous injections are administered for enzyme replacement therapy, then adequate GCase levels are maintained in patients, but treatment duration and frequency create lifelong burden
Solution Approach 1:
The invention implements continuity of useful action by establishing permanent endogenous GCase production within patient cells through gene transfer. Once the functional gene is integrated into the patient's cells, it continuously produces the therapeutic enzyme throughout the patient's lifetime, eliminating the need for repeated dosing and providing uninterrupted therapeutic effect.
Data Source
AI summary
The present invention relates to polynucleotides comprising a GBA nucleotide sequence that encodes a GCase protein or fragment thereof and wherein a portion of the coding sequence is not wild type. The present invention further relates to viral particles comprising a recombinant genome comprising the polynucleotide of the invention, compositions comprising the polynucleotides or viral particles, and methods and uses of the polynucleotides, viral particles or compositions.