NADPH Augmentation for Neurodegenerative Mitochondrial Disease

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Solution Overview

Problem

Mitochondrial diseases, particularly neurodegenerative mitochondrial diseases, lack effective therapeutic, diagnostic, and prognostic strategies due to poorly understood molecular mechanisms governing these conditions, with existing treatments focusing on ATP depletion despite evidence challenging this perception.

Innovation Solution

The method involves augmenting NADPH levels by increasing the expression and/or activity of enzymes like ME1, IDH1, or G6PD, using an adeno-associated virus with CNS tropism, to address the decline in NADPH levels rather than ATP, which is responsible for reduced cellular fitness in ETC-impaired cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If ATP depletion is targeted as the main contributor to pathology, then therapeutic strategies focus on energy replacement, but this approach fails to address the actual molecular mechanisms and shows limited therapeutic efficacy

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidmolecular mechanism understanding

Core Design Contradiction:

ReliabilityVSLoss of information

Solution Approach 1:

The patent inverts the conventional approach by shifting focus from ATP levels to NADPH levels. Instead of treating ATP depletion as the primary problem, the invention identifies NADPH deficiency as the actual cause of reduced cellular fitness in ETC-impaired cells, thereby reversing the therapeutic target and achieving better efficacy

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent changes the key parameter from ATP concentration to NADPH concentration. By measuring and targeting NADPH levels instead of ATP levels, the invention identifies the true metabolic defect in mitochondrial diseases and develops therapies based on this corrected parameter

Inventive Principle:

Principle #35Parameter changes

2Ease of manufacture

If existing treatments focus on ATP depletion, then therapeutic approaches are limited to energy replacement, but this ignores the actual cause of reduced cellular fitness

Engineering Contradiction:

Improvetreatment availabilityVSAvoidtherapeutic effectiveness

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent substitutes the mechanical/chemical approach of ATP replacement with a metabolic approach targeting NADPH regeneration. Instead of simply providing energy substrates, the invention activates specific metabolic pathways (PPP, ME1, IDH1) to regenerate NADPH, replacing an ineffective mechanism with a biologically targeted one

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Loss of information

If the dogma of ATP depletion is maintained, then research continues along unproductive lines, but recent evidence challenges this perception without providing alternative explanations

Engineering Contradiction:

Improvemolecular mechanism knowledgeVSAvoidtherapeutic development progress

Core Design Contradiction:

Loss of informationVSProductivity

Solution Approach 1:

The patent introduces feedback by measuring NADPH levels and using this information to guide therapeutic intervention. The method assesses NADPH status in patients and tailors treatment accordingly, creating a feedback loop that connects molecular measurement to clinical decision-making, thereby advancing both understanding and therapeutic productivity

Inventive Principle:

Principle #23Feedback

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

This approach suppresses neuroinflammation, corrects motor function, and improves coordination in preclinical models by specifically targeting NADPH levels, providing a cohesive explanation for differential brain cell sensitivities to ETC inhibition.

Implementation Method 1

using an adeno-associated virus with CNS tropism

Methodology Applied

Scientific EffectViral transduction:

Implementation Method 2

increasing the expression and/or activity of enzymes like ME1, IDH1, or G6PD

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Implementation Method 3

augmenting NADPH levels by increasing the expression and/or activity of enzymes that produce NADPH, preferably by means of the administration of a vector to deliver and enhance the expression and/or activity of enzymes that produce NADPH in the brain

Methodology Applied

Scientific EffectMalic enzyme reaction: Enzyme

Implementation Method 4

augmenting NADPH levels by increasing the expression and/or activity of enzymes that produce NADPH

Methodology Applied

Scientific EffectPentose phosphate pathway reaction: Enzyme

Data Source

PatentEP4653001A1Treatment, diagnosis and/or prognosis of mitochondrial diseases

Publication Date: 2025.11.26 AUTONOMOUS UNIVERSITY OF MADRID

Figure 1A~1B
Figure 1C~1D
Figure 1E

AI summary

The present invention refers to a method for the treatment, diagnosis and/or prognosis of mitochondrial diseases (i.e., pathologies associated with mitochondrial dysfunction), preferably for the treatment, diagnosis and/or prognosis of neurodegenerative mitochondrial diseases (i.e., treatment, diagnosis and/or prognosis of neuroinflammation and/or neurodegeneration in the context of those mitochondrial diseases).