AAV Capsid Targeting Peptides for Precise Retinal Gene Delivery
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Solution Overview
Problem
Existing adeno-associated virus (AAV) vectors exhibit unpredictable effects due to differences in polypeptides inserted into the capsid protein, leading to off-target gene delivery and adverse effects, necessitating the development of modified AAV capsid proteins for improved targeting capability, particularly for eye-specific delivery.
Innovation Solution
Designing AAV capsid proteins with specific targeting peptides inserted or substituted at the 586th and 587th amino acids, such as sequences AAX1X2X3X4X5X6X7X8AA and NG, to enhance retinal transduction efficiency and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If wild-type AAV capsid protein is used, then broad tissue targeting capacity is achieved, but off-target gene delivery occurs leading to adverse effects
Solution Approach 1:
The patent applies local quality by inserting specific polypeptide sequences (targeting peptides) at defined positions (amino acid residues 586-588) of the AAV capsid protein. This localized modification at the capsid surface enables specific recognition and binding to retinal cells while maintaining overall capsid structure, thereby achieving eye-specific targeting without broad tissue tropism and preventing off-target delivery
Solution Approach 2:
The patent employs parameter changes by systematically varying the amino acid sequences inserted at positions 586-588 of the capsid protein. Different polypeptide compositions (including sequences with RGD structures) are tested to optimize binding affinity and specificity for retinal cells, thereby tuning the targeting parameters to achieve high-efficiency eye-specific delivery
2Manufacturing precision
If polypeptides are inserted into AAV capsid protein to improve targeting, then tissue specificity is enhanced, but effects become unpredictable
Solution Approach 1:
The patent applies preliminary action by conducting extensive in silico screening and in vitro validation before in vivo application. The patent systematically evaluates multiple polypeptide sequences (including 15 different sequences) for their ability to bind retinal cells, selecting only those that demonstrate consistent and predictable targeting effects. This preliminary characterization establishes structure-activity relationships that enable predictable design of eye-specific AAV vectors
Solution Approach 2:
The patent uses intermediary by employing a standardized polypeptide insertion framework at the capsid surface. The inserted polypeptides act as intermediaries that mediate specific interactions between the AAV capsid and retinal cell surface receptors. This standardized intermediary approach (inserting defined sequences at positions 586-588) creates reproducible and predictable targeting effects across different AAV serotypes
Data Source
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AI summary
Provided are an adeno-associated virus capsid protein, an adeno-associated virus containing same, a vector, and the use thereof. Specifically, provided is an adeno-associated virus capsid protein comprising a targeting peptide. The targeting peptide contains one or more of the following sequences: (i) sequence AAX1X2X3X4X5X6X7X8AA; and (ii) sequence NG. Further provided are a targeting peptide, an adeno-associated virus, a transgenic delivery vector, a pharmaceutical composition, etc. Compared with a wild-type adeno-associated virus, the provided adeno-associated virus capsid protein and the adeno-associated virus containing same have improved cell infection efficiency in vivo and/or in vitro, have a good targeting effect on eyes, and can be used as a delivery vector for the treatment of eye-related diseases.