Variant AAV Capsid Mutations for Higher CNS Transduction

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Solution Overview

Problem

Existing adeno-associated dependoparvoviruses (AAVs) face challenges in achieving optimal central nervous system (CNS) biodistribution and transduction efficiency.

Innovation Solution

Development of variant capsid proteins, such as VP1, VP2, and VP3, with specific mutations at positions 579, 592, 593, 595, 596, and 598, enhancing CNS biodistribution and transduction efficiency compared to wild-type AAVs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If wild-type AAV capsid proteins are used, then the virus can be produced and delivered to cells, but the central nervous system biodistribution and transduction efficiency are suboptimal

Engineering Contradiction:

ImproveCNS biodistribution and transduction efficiencyVSAvoidcell expression level in brain regions

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies parameter changes by introducing specific amino acid mutations at positions 579, 592, 593, 595, 596, and 598 in the capsid protein sequence. These mutations alter the physical-chemical properties of the capsid surface, enabling enhanced interaction with CNS cellular targets and improving transduction efficiency up to 25-fold compared to wild-type AAVs

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention applies local quality by making site-specific modifications only at particular residues (579, 592, 593, 595, 596, 598) within the capsid protein rather than global changes. This targeted approach optimizes local interaction interfaces with CNS cells while preserving the overall capsid structure and function

Inventive Principle:

Principle #3Local quality

2Reliability

If capsid protein mutations are introduced to enhance CNS transduction, then transduction efficiency improves, but the complexity of protein production increases

Engineering Contradiction:

Improvetransduction efficiencyVSAvoidcapsid protein production complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the capsid protein into functional domains, with specific focus on the VP1, VP2, and VP3 variants. The mutations are introduced as discrete, modular changes at specific positions, allowing for systematic production and characterization of each variant form

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention applies copying by creating multiple variant capsid proteins (VP1, VP2, VP3) based on the wild-type sequence template. Each variant is a copy with specific mutations, enabling parallel production and comparison of different capsid configurations to optimize CNS delivery

Inventive Principle:

Principle #26Copying

Data Source

PatentUS12528841B2Capsid variants and methods of using the same

Publication Date: 2026.01.20 DYNO THERAPEUTICS INC

AI summary

The disclosure is directed in part to variant capsid polypeptides that can be used to deliver payloads.