Engineered AAV Capsids for Inner Limiting Membrane Penetration

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Solution Overview

Problem

Current AAV vectors face challenges in effectively penetrating the inner limiting membrane (ILM) and achieving gene transfer across the entire retina, particularly for inner retinal cells and photoreceptors, leading to suboptimal retinal thickness and visual acuity, especially when administered intravitreally.

Innovation Solution

Engineering AAV capsids with peptide inserts at specific positions, such as 453 or 587/588, to enhance retinal penetration and transduction efficacy, reducing binding to heparan sulfate proteoglycan and improving viral delivery across the retina.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Area of stationary object

If AAV vectors are administered intravitreally, then delivery to the entire retina is achieved, but penetration through the inner limiting membrane is hindered due to abundant native receptors

Engineering Contradiction:

Improveretinal coverage areaVSAvoidILM penetration efficiency

Core Design Contradiction:

Area of stationary objectVSReliability

Solution Approach 1:

The patent applies local quality by modifying specific regions of the AAV capsid protein (positions 453 and 587/588) with peptide inserts. These localized modifications change the interaction properties at specific sites on the capsid surface, enabling selective penetration through the ILM while maintaining overall capsid structure and function.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent changes the chemical and physical parameters of the AAV capsid by introducing peptide sequences that alter receptor binding characteristics. This modifies the interaction between the virus and the inner limiting membrane, transforming the capsid's ability to penetrate through this barrier while maintaining systemic delivery capabilities.

Inventive Principle:

Principle #35Parameter changes

2Manufacturing precision

If subretinal application is used, then gene transfer to cells adjacent to injected fluid is achieved, but retinal thickness decreases and visual acuity is reduced

Engineering Contradiction:

Improvegene transfer precisionVSAvoidretinal damage

Core Design Contradiction:

Manufacturing precisionVSObject-affected harmful factors

Solution Approach 1:

The patent uses engineered peptide sequences as intermediaries that mediate the interaction between AAV vectors and retinal cells. These peptide inserts act as molecular mediators that facilitate vector penetration through the ILM and enable safe intravitreal delivery, avoiding direct subretinal injection and its associated harmful effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Ease of operation

If native AAV receptors are present on the ILM, then intravitreal injection is safer and easier, but vector penetration through the ILM is blocked

Engineering Contradiction:

Improveinjection safety and easeVSAvoidvector penetration efficiency

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent applies inversion by reversing the typical problem-solution approach. Instead of trying to overcome the presence of native receptors as a barrier, the invention utilizes the intravitreal route (which is safer and easier) and modifies the vector to actively engage with or bypass these receptors, transforming the barrier into a permeable pathway.

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS12509705B2AAV vector variants for ocular gene delivery

Publication Date: 2025.12.30 MEDIZINISCHE HOCHSCHULE HANNOVER

AI summary

The present invention relates to adeno-associated virus capsid polypeptide sequences and their use in therapeutic transgene delivery to the eye and potentially other tissues.