AAV Capsid Mutations for Tissue-Targeted Gene Delivery

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Solution Overview

Problem

There is a need to improve the delivery efficiency and tissue targeting of adeno-associated virus (AAV) vectors for gene delivery, as existing technologies are limited in their ability to selectively target specific tissues and optimize payload packaging.

Innovation Solution

Engineering viral vectors with capsid polypeptide mutations in the region corresponding to amino acids 561-588, specifically altering the tropism of AAV particles to enhance tissue targeting and payload packaging efficiency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If wild-type AAV capsid polypeptide is used, then the viral vector can deliver DNA payload, but the delivery efficiency and tissue targeting are limited

Engineering Contradiction:

Improvedelivery efficiencyVSAvoidtissue targeting specificity

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies parameter changes by introducing specific amino acid mutations in the capsid polypeptide sequence (particularly in the P2 domain at positions 561-588). These mutations alter the physical-chemical properties of the capsid surface, enabling improved tissue targeting and delivery efficiency while maintaining viral vector functionality

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention implements local quality by making targeted mutations at specific regions of the capsid polypeptide (amino acid positions 561-588 in the P2 domain) rather than modifying the entire structure. This localized modification approach allows optimization of tissue targeting properties while preserving overall capsid function and payload delivery capability

Inventive Principle:

Principle #3Local quality

2Reliability

If capsid polypeptide mutations are introduced to modify tropism, then tissue targeting is improved, but the structural integrity of the viral capsid may be compromised

Engineering Contradiction:

Improvetissue targetingVSAvoidcapsid structural integrity

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent carefully selects amino acid substitutions that change the surface properties and tropism of the capsid without disrupting the core structural framework. Mutations are introduced at positions 561-588 that modify tissue targeting while maintaining capsid stability through conservative substitution strategies

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention employs computational design and modeling to predict mutations that will improve tissue targeting while preemptively assessing their potential impact on structural integrity. This allows selection of mutations that are cushioned against destabilizing effects, ensuring capsid stability is maintained while achieving improved tropism

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

Data Source

PatentUS12617821B2Engineered viral capsid polypeptides and uses thereof

Publication Date: 2026.05.05 PRESIDENT & FELLOWS OF HARVARD COLLEGE

AI summary

The technology described herein provides variant adeno-associated viral capsid polypeptides and viruses comprising the same. Such variant viral capsid polypeptides bear a mutation relative to SEQ ID NO: 2 (WT AAV2) in a region corresponding to amino acids 561-588, wherein the region corresponding to amino acids 561-588 comprises a sequence selected from SEQ ID NO: 4-41,337. Further provided herein are methods for delivering a viral payload using viruses comprising variant capsid polypeptides described herein.