Codon-Optimized rAAV Vector for LCA Treatment
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Solution Overview
Problem
Current treatments for Leber congenital amaurosis (LCA), a rare hereditary ocular disease leading to severe visual impairment and blindness, are inadequate in effectively addressing the genetic defects causing the condition.
Innovation Solution
A recombinant adeno-associated virus (rAAV) particle is developed, containing a codon-optimized expression cassette with an altered number of CpG dinucleotides in the RPE65 coding sequence, which is designed to be administered via intravitreal, subretinal, or suprachoroidal injection to treat LCA by providing functional RPE65 protein to ocular cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If a wild type RPE65 nucleotide sequence is used in the expression cassette, then the sequence maintains natural biological properties, but the immunogenicity increases due to high CpG dinucleotide content
Solution Approach 1:
The patent applies parameter changes by modifying the nucleotide sequence composition, specifically reducing CpG dinucleotide content from the wild type sequence. This changes the chemical parameters of the DNA sequence while maintaining the amino acid coding capacity, thereby reducing immunogenicity without altering the fundamental RPE65 protein function
Solution Approach 2:
The patent creates a modified copy of the wild type RPE65 nucleotide sequence that encodes the same amino acid sequence but with altered nucleotide composition. This copying approach allows the therapeutic gene to maintain its functional properties while having reduced immunogenicity through the modified nucleotide sequence
2Reliability
If the RPE65 gene is delivered via AAV vector to treat LCA, then functional RPE65 protein can be provided to ocular cells, but the treatment complexity increases due to gene delivery requirements
Solution Approach 1:
The patent uses adeno-associated virus (AAV) as an intermediary vector to deliver the RPE65 gene to ocular cells. The AAV vector serves as a mediator that facilitates safe and effective gene delivery to the retina, bridging the gap between the therapeutic gene and the target cells without requiring complex direct gene insertion methods
3Productivity
If codon optimization is applied to the RPE65 coding sequence, then protein expression efficiency is improved, but the nucleotide sequence diverges further from the wild type
Solution Approach 1:
The patent applies codon optimization by changing the nucleotide composition of the RPE65 coding sequence to use codons that are more efficiently translated by human cellular machinery. This parameter change in nucleotide sequence composition improves protein expression efficiency while maintaining the same amino acid sequence through synonymous codon substitutions
Data Source
AI summary
The present disclosure relates to a pharmaceutical composition for the treatment of Leber congenital amaurosis, and a method for treating Leber congenital amaurosis using the pharmaceutical composition.