Codon-optimized reduced-size ATP7A nucleic acids for AAV delivery
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Solution Overview
Problem
Current treatments for ATP7A-related copper transport disorders, such as Menkes disease and occipital horn syndrome, are inadequate in addressing the impaired copper transport and resulting neurological and developmental issues.
Innovation Solution
The development of codon-optimized ATP7A nucleic acid molecules encoding a reduced-size ATP7A protein, which are used in vectors and recombinant viruses, specifically adeno-associated virus (AAV) vectors, to be administered to subjects for treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If codon-optimized nucleic acid encoding reduced-size ATP7A is delivered via AAV vector, then copper transport function is improved, but vector capacity is limited
Solution Approach 1:
The patent extracts and removes portions of the ATP7A protein sequence that are non-essential for copper transport function, creating a reduced-size protein variant. This extraction allows the gene to fit within the limited AAV vector capacity while preserving the essential copper transporting activity of the full-length protein.
Solution Approach 2:
The patent applies codon optimization specifically to the reduced-size ATP7A gene sequence, tailoring the nucleotide composition to enhance expression efficiency in human cells. This local optimization of the gene's nucleotide sequence improves protein production without increasing the physical size of the genetic material, resolving the capacity constraint.
2Reliability
If full-length ATP7A gene is used, then complete copper transport activity is achieved, but gene size exceeds AAV vector capacity
Solution Approach 1:
The patent extracts and removes portions of the ATP7A protein sequence that are non-essential for copper transport function, creating a reduced-size protein variant. This extraction allows the gene to fit within the limited AAV vector capacity while preserving the essential copper transporting activity of the full-length protein.
Solution Approach 2:
The patent employs a partial version of the ATP7A protein (reduced-size variant) that contains only the essential domains required for copper transport function. This partial action approach achieves sufficient therapeutic effect without requiring the complete gene sequence, enabling AAV vector delivery.
3Productivity
If native nucleic acid sequence is used, then natural expression patterns are maintained, but expression efficiency is insufficient
Solution Approach 1:
The patent changes the nucleotide composition parameters of the ATP7A gene through codon optimization, replacing rare codons with more frequently used codons in human cells. This parameter change in the nucleic acid sequence dramatically improves translation efficiency and protein expression levels while maintaining the identical amino acid sequence and thus the protein's functional properties.
Data Source
AI summary
Disclosed herein are codon-optimized nucleic acids encoding a reduced-size ATP7A protein. Also disclosed are vectors and recombinant viruses (such as recombinant adeno-associated viruses) including the codon-optimized nucleic acids encoding the reduced-size ATP7A protein and compositions including the disclosed vectors and viruses. Further disclosed herein are methods of treating copper transport disorders, for example by administering a disclosed nucleic acid, vector, or recombinant virus to a subject with a copper transport disorder, such as Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy.