AAV Capsid Peptide Insertions for Eye-Targeted Gene Delivery
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Solution Overview
Problem
Existing AAV vectors lack sufficient specificity and efficiency for targeted delivery to the eye, particularly for ocular diseases, necessitating improved eye-targeted gene therapy.
Innovation Solution
A variant AAV capsid polypeptide with a peptide insertion in variable regions IV or VIII, featuring specific amino acid sequences (SEQ ID NOs: 1-29) or sequences with at least 70-85% identity, enhancing targeting and transduction to eye cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type AAV capsid polypeptide is used, then the vector is simple and easy to manufacture, but the targeting specificity and transduction efficiency to eye cells are insufficient
Solution Approach 1:
The patent applies local quality by introducing a peptide insertion specifically in variable region IV or VIII of the AAV capsid polypeptide. This localized modification enhances targeting specificity to eye cells without requiring complete redesign of the entire capsid structure, thus improving reliability while maintaining manageable complexity.
Solution Approach 2:
The patent utilizes parameter changes by modifying the amino acid sequence at specific positions (variable region IV or VIII) of the capsid polypeptide. This controlled parameter modification in the capsid structure enables improved binding affinity and transduction efficiency to eye cells, resolving the contradiction between simplicity and effectiveness.
2Productivity
If wild-type AAV capsid polypeptide is used, then the manufacturing process is simple, but the transduction efficiency to eye cells is insufficient
Solution Approach 1:
The peptide insertion in variable region IV or VIII provides localized functional enhancement for transduction efficiency. This approach maintains the overall simplicity of the capsid structure and manufacturing process while significantly improving the ability to transduce eye cells, thus resolving the contradiction between productivity and ease of manufacture.
3Measurement precision
If existing AAV vectors are used, then the delivery system is straightforward, but the targeting precision to ocular diseases is insufficient
Solution Approach 1:
The patent implements local quality by introducing a specific peptide insertion in variable region IV or VIII of the capsid polypeptide. This localized modification enhances targeting precision to ocular tissues and disease-affected areas without requiring complex modifications to the entire vector structure, thus improving measurement precision while maintaining vector simplicity.
Data Source
AI summary
The present application relates to (i) a variant adeno-associated virus (AAV) capsid polypeptide comprising a peptide insertion in the variable region IV or in the variable region VIII relative to a wild-type AAV capsid polypeptide, wherein the peptide insertion comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-29 or an amino acid sequence having at least 70% sequence identity thereto, (ii) an isolated nucleic acid encoding the aforementioned variant polypeptide, (iii) a recombinant polynucleotide comprising the aforementioned nucleic acid, and (iv) an isolated cell comprising the aforementioned polypeptide, nucleic acid or recombinant polynucleotide. The present application further relates to (v) an adeno-associated virus (AAV) vector comprising the aforementioned variant polypeptide, (vi) a pharmaceutical composition comprising the aforementioned AAV vector as well as (vii) the use of the aforementioned vector or pharmaceutical composition in preventing or treating an ocular disease. Finally, the present application relates to (viii) a method of delivering a heterologous nucleic acid to a retinal cell and (ix) a method of delivering a heterologous nucleic acid to the eye of a subject.