AAV9 PLA2G6 Gene Therapy Without WPRE for Safer INAD Expression

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Solution Overview

Problem

Infantile neuroaxonal dystrophy (INAD) is an extremely rare and rapidly progressing disorder with limited treatment options, primarily affecting the nervous system and leading to severe developmental delays and early mortality due to mutations in the PLA2G6 gene, lacking effective therapeutic interventions.

Innovation Solution

A gene therapy approach using an AAV9 capsid vector containing an expression cassette without a woodchuck hepatitis virus post-transcriptional regulatory element (WPRE), comprising a SYN1 or EF1a promoter, and encoding the wildtype PLA2G6 gene to restore enzyme function in various tissues, including neuronal and muscular tissues.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a viral vector includes a woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) to enhance transgene expression, then mRNA stability and transgene expression are improved, but oncogenic potential increases making it unsuitable for clinical use

Engineering Contradiction:

Improvetransgene expression levelVSAvoidoncogenic potential

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent removes the WPRE element from the expression cassette to eliminate oncogenic potential while maintaining sufficient transgene expression through alternative means, specifically using strong promoters (SYN1 or EF1a) and optimized poly(A) signals without relying on the problematic WPRE sequence

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent employs a simplified expression cassette design that uses conventional, well-characterized elements (promoters, poly(A) signals) that are safer and more suitable for clinical use, replacing the complex and potentially harmful WPRE element with simpler, safer alternatives that achieve the necessary expression levels

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Reliability

If gene therapy is developed for INAD, then treatment effectiveness is improved, but development investment is limited due to the rare and clinically diverse patient population

Engineering Contradiction:

Improvetreatment effectivenessVSAvoiddevelopment investment

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent designs a universal expression cassette that can be applied across different INAD patient subtypes through the use of broadly active promoters (SYN1 for neuronal tissues, EF1a for multiple tissue types), making the therapy applicable to the diverse clinical phenotypes observed in INAD patients without requiring separate development for each subtype

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent optimizes the expression cassette parameters (promoter selection, poly(A) signal positioning, absence of WPRE) to achieve sufficient transgene expression levels that can address the diverse clinical presentations of INAD, thereby improving treatment effectiveness across the patient population

Inventive Principle:

Principle #35Parameter changes

3Object-affected harmful factors

If the expression cassette lacks WPRE to ensure clinical safety, then oncogenic potential is reduced, but transgene expression may be insufficient

Engineering Contradiction:

Improveoncogenic potentialVSAvoidtransgene expression level

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent combines strong promoters (SYN1 or EF1a) with optimized poly(A) signals and other expression-enhancing elements to compensate for the absence of WPRE, achieving sufficient transgene expression levels through the synergistic action of multiple safe and effective components

Inventive Principle:

Principle #5Merging (Combining)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The gene therapy effectively restores PLA2G6 enzyme activity, potentially slowing disease progression and improving patient outcomes by addressing the genetic cause of INAD, as demonstrated in pre-clinical mouse models.

Implementation Method 1

Gene therapies of the invention provide a wildtype copy of the PLA2G6 gene to the correct cell types at the correct level

Methodology Applied

Scientific EffectGene therapy:

Implementation Method 2

A gene therapy approach using an AAV9 capsid vector containing an expression cassette

Methodology Applied

Scientific EffectViral vector delivery:

Implementation Method 3

By providing an additional wildtype copy of the PLA2G6 gene, A2 phospholipase expression can be restored

Methodology Applied

Scientific EffectTranscription and translation:

Implementation Method 4

A2 phospholipase, involved in metabolizing phospholipids

Methodology Applied

Scientific EffectEnzyme function restoration: Enzyme

Data Source

PatentUS20260002174A1Gene therapies for treatment of infantile neuroaxonal dystrophy

Publication Date: 2026.01.01 INADCURE FOUNDATION INC

AI summary

The present invention provides gene therapies for the treatment of Infantile Neuroaxonal Dystrophy. The invention provides a viral vector comprising a viral capsid and an expression cassette comprising a nucleic acid encoding the PLA2G6 gene. The expression cassette comprises, in order, a SYN1 promoter or an EF1a promoter, a nucleic acid sequence encoding a PLA2G6 gene, and a poly(A) signal. Advantageously, the expression cassette does not comprise a woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) between the nucleic acid sequence encoding a PLA2G6 gene and the poly(A) signal.