Codon-Optimized Yeast NDI1 Gene Variants for Mitochondrial Therapy
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Solution Overview
Problem
Current gene therapies for Leber hereditary optic neuropathy (LHON) face challenges in delivering therapies to retinal ganglion cells and are hindered by intragenic heterogeneity and the need for mitochondrial targeting, with existing delivery methods not being readily translatable to human patients.
Innovation Solution
Development of codon-optimized and immune-optimized variants of the yeast NDI1 gene for improved expression and reduced immunogenicity in mammalian cells, combined with the use of adeno-associated virus (AAV) vectors for targeted delivery to retinal ganglion cells, enhancing mitochondrial function and reducing oxidative stress.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If yeast NDI1 gene is used for therapy, then mitochondrial function is restored, but immunogenicity increases and expression efficiency decreases
Solution Approach 1:
The patent applies codon optimization to change the nucleotide sequence parameters of the yeast NDI1 gene without altering the amino acid sequence. This modifies the gene's expression characteristics in mammalian cells, improving translation efficiency and reducing immunogenicity while preserving the therapeutic protein function.
Solution Approach 2:
The patent creates a modified copy of the yeast NDI1 gene by replacing yeast-specific codons with mammalian-preferred codons. This copied version maintains the same protein-coding information but is optimized for mammalian cellular machinery, reducing immune recognition while preserving therapeutic effect.
2Reliability
If yeast NDI1 gene is used for therapy, then mitochondrial function is restored, but expression efficiency in mammalian cells decreases
Solution Approach 1:
The patent optimizes codon usage parameters to match mammalian cell preferences. By统计分析 mammalian codon usage frequencies and replacing yeast-specific codons, the gene achieves higher translation efficiency and protein expression levels in mammalian cells while maintaining the same amino acid sequence and therapeutic function.
3Reliability
If current gene therapy delivery methods are used, then some mitochondrial targeting is achieved, but delivery to retinal ganglion cells is insufficient and not translatable to humans
Solution Approach 1:
The patent uses adeno-associated virus (AAV) vectors as intermediary delivery vehicles. These vectors are engineered to specifically target retinal ganglion cells and facilitate efficient gene transfer, bridging the gap between systemic administration and cellular-level mitochondrial therapy in a clinically translatable manner.
Data Source
AI summary
An isolated nucleic acid sequence encoding the yeast NDI1 protein of SEQ ID NO: 542 or a functional variant thereof is described. The nucleic acid sequence comprises at least 50 codons which are codon optimized compared with the sequence of yeast NDI1 gene of SEQ ID NO: 1.