BVES Gene Therapy With Muscle-Specific AAV Expression

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Solution Overview

Problem

There are no effective treatments for BVES-related disorders such as limb-girdle muscular dystrophy type R25, which are caused by genetic mutations in the BVES gene, leading to muscle degeneration and heart rhythm abnormalities.

Innovation Solution

Administration of a therapeutically effective amount of an expression vector containing a nucleic acid encoding the BVES protein, linked to a muscle-specific promoter and an inverted terminal repeat sequence, delivered via a viral vector like AAV, to restore BVES function in subjects with mutated BVES genes, optionally combined with a proteasome inhibitor like bortezomib.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Strength

If gene therapy using expression vectors is administered to restore BVES function, then muscle function and mass are improved, but the complexity of treatment protocols increases

Engineering Contradiction:

Improvemuscle functionVSAvoidtreatment protocol complexity

Core Design Contradiction:

StrengthVSDevice complexity

Solution Approach 1:

The patent employs viral vectors (AAV) as intermediaries to deliver the BVES expression vector into muscle cells. This intermediary approach simplifies the treatment protocol by using a well-established delivery mechanism that can be administered via simple intramuscular injection, avoiding complex surgical or invasive procedures while still achieving effective gene restoration.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The expression vector is designed with a muscle-specific promoter that automatically ensures BVES protein is expressed only in muscle tissues after delivery. This self-regulating mechanism eliminates the need for complex monitoring or control systems, allowing the therapy to autonomously restore function in the affected tissue without requiring additional regulatory interventions.

Inventive Principle:

Principle #25Self-service

2Reliability

If expression vector is administered to treat BVES-related disorders, then muscle atrophy is reduced, but the risk of unintended tissue expression increases

Engineering Contradiction:

Improvemuscle mass maintenanceVSAvoidunintended tissue expression

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs a muscle-specific promoter (such as the MyoD1 or MHC promoter) that is naturally active only in muscle tissues. This local quality approach ensures that the BVES protein is expressed exclusively in muscle cells where it is needed, preventing unintended expression in other tissues while maintaining reliable muscle mass maintenance and function restoration.

Inventive Principle:

Principle #3Local quality

3Productivity

If proteasome inhibitor is combined with expression vector, then treatment effectiveness is enhanced, but the complexity of combination therapy increases

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidcombination therapy complexity

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent proposes administering the proteasome inhibitor before or concurrent with the expression vector delivery to preemptively clear existing mutant BVES proteins and reduce proteasomal degradation pathways. This preliminary action enhances the effectiveness of the gene therapy by ensuring that the restored BVES protein is not immediately degraded, while the combination can be simplified through a single sequential administration protocol rather than requiring complex ongoing combination regimens.

Inventive Principle:

Principle #10Preliminary action

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 method significantly improves muscle function and mass, reduces muscle atrophy, and ameliorates heart rhythm abnormalities by restoring BVES expression and regulating cAMP/PKA signaling, thereby addressing the progression of BVES-related disorders.

Implementation Method 1

administering to the subject a therapeutically effective amount of an expression vector comprising a nucleic acid encoding a blood vessel epicardial substance (BVES) protein

Methodology Applied

Scientific EffectGene expression:

Implementation Method 2

the expression vector is a viral vector. In some embodiments, the viral vector is an adeno-associated virus (AAV) vector

Methodology Applied

Scientific EffectViral vector delivery:

Implementation Method 3

the method of any preceding aspect further comprises administering to the subject a therapeutically effective amount of a proteasome inhibitor

Methodology Applied

Scientific EffectProteasome inhibition:

Implementation Method 4

ameliorates heart rhythm abnormalities by restoring BVES expression and regulating cAMP/PKA signaling

Methodology Applied

Scientific EffectcAMP signaling:

Data Source

PatentUS20250340902A1Gene therapy for BVES-related disorders

Publication Date: 2025.11.06 OHIO STATE INNOVATION FOUND

AI summary

The present disclosure relates to compositions and methods for treating blood vessel epicardial substance (BVES) protein-related disorders.