Codon-Optimized FVIII-BDD Nucleic Acid for Higher Expression
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Solution Overview
Problem
Current gene therapy approaches for haemophilia A, such as AAV-based vectors encoding FVIII, face challenges in maintaining sufficient expression levels of coagulation factor VIII, leading to costly and inefficient treatment with potential complications, and there is a need for improved gene therapy products.
Innovation Solution
Development of codon-optimized nucleic acids encoding FVIII-BDD protein, specifically variants with sequences SEQ ID NO: 2, 3, 4, or 5, which enhance gene expression and protein production levels, integrated into expression cassettes and vectors for increased therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AAV-based vectors encoding wild-type FVIII gene are used for gene therapy, then the treatment can be administered, but the expression levels of coagulation factor VIII are insufficient
Solution Approach 1:
The patent applies codon optimization to change the nucleotide sequence parameters of the FVIII gene while maintaining the same amino acid sequence. This parameter change in the genetic code improves translation efficiency and protein expression levels, directly resolving the contradiction between insufficient expression levels and productivity
Solution Approach 2:
The patent creates optimized copies of the wild-type FVIII gene with improved codon usage patterns. These copied sequences maintain the same protein function but exhibit enhanced expression characteristics, allowing the system to achieve higher productivity while maintaining reliability
2Reliability
If lifelong replacement therapy with recombinant FVIII injections is administered, then patients receive necessary treatment, but the treatment cost becomes very expensive
Solution Approach 1:
The patent implements preliminary action by using gene therapy to establish permanent or long-lasting FVIII production capacity within the patient's cells. This preliminary genetic modification eliminates the need for repeated injections, reducing treatment frequency from lifelong regular administration to a single or limited number of administrations
Solution Approach 2:
The patent enables the patient's own cells to produce the necessary coagulation factor VIII through introduced and optimized genes. This self-service mechanism allows the body to generate its own therapeutic protein, eliminating dependence on external injections and significantly reducing treatment frequency and associated costs
3Reliability
If replacement therapy is administered every 3 days, then FVIII activity is maintained, but complications such as haemarthrosis and inhibitor development still occur
Solution Approach 1:
The patent applies preliminary action by establishing endogenous FVIII production capacity before complications can develop. By genetically modifying cells to produce FVIII continuously, the therapy prevents rather than treats haemarthrosis and reduces the risk of inhibitor development through more physiological, sustained protein levels
Solution Approach 2:
The patent creates a feedback system where the patient's own cells continuously produce and regulate FVIII levels based on cellular metabolism and protein folding mechanisms. This endogenous feedback control maintains more natural and stable FVIII activity levels compared to exogenous injection cycles, reducing harmful fluctuations that lead to complications
Data Source
AI summary
The present application relates to the fields of genetics, gene therapy, and molecular biology. More specifically, the present invention relates to a codon-optimized nucleic acid that encodes the FVIII-BDD (B-domain deleted coagulation factor VIII) protein, to an expression cassette and a vector based thereon, to a host cell for producing FVIII-BDD, as well as to various uses of the above vector.