GUK1-Related MDDS Therapy Using Deoxyguanosine and PNP Inhibition

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Solution Overview

Problem

Mitochondrial DNA depletion-deletions syndromes (MDDS) caused by mutations in the GUK1 gene lead to unbalanced nucleotide pools, affecting skeletal muscle, brain, peripheral nerves, kidney, and liver, with no effective pharmacological treatments available.

Innovation Solution

Administering a therapeutically effective amount of deoxyguanosine (dG) and/or a purine nucleoside phosphorylase (PNP) inhibitor, such as forodesine, to correct the nucleotide imbalance and increase mtDNA levels.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If deoxynucleosides and PNP inhibitors are administered to treat MDDS caused by GUK1 mutations, then mtDNA levels increase and symptoms are alleviated, but no effective pharmacological treatments were previously available

Engineering Contradiction:

Improvetreatment efficacyVSAvoidpharmacological treatment availability

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention changes the chemical parameters of nucleotide metabolism by administering deoxynucleosides (specifically deoxyguanosine) and PNP inhibitors (such as forodesine) to alter the nucleotide pool balance. This pharmacological intervention shifts the metabolic parameters to compensate for GUK1 enzyme deficiency, thereby increasing mtDNA levels and treating the underlying cause of MDDS

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention uses deoxynucleosides and PNP inhibitors as intermediary substances that mediate between the defective GUK1 enzyme function and the required nucleotide pool balance. These compounds act as pharmacological mediators to restore proper nucleotide metabolism and support mtDNA synthesis in the absence of functional GUK1

Inventive Principle:

Principle #24Intermediary (Mediator)

2Stability of the object's composition

If pharmacological treatment is developed for GUK1-related MDDS, then unbalanced nucleotide pools can be corrected, but previously no effective treatments existed for this condition

Engineering Contradiction:

Improvenucleotide pool balanceVSAvoidtreatment development

Core Design Contradiction:

Stability of the object's compositionVSEase of manufacture

Solution Approach 1:

The invention applies parameter changes by modifying the nucleotide pool composition through pharmacological administration. Deoxynucleosides and PNP inhibitors alter the concentration parameters of various nucleotides, shifting the system from an unbalanced state (caused by GUK1 deficiency) to a balanced state that supports normal mtDNA synthesis

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention converts the harmful effect of GUK1 deficiency (nucleotide pool imbalance leading to mtDNA depletion) into a treatable condition by using PNP inhibitors. The inhibitor blocks the degradation pathway, thereby benefiting from the same metabolic pathway that causes harm when unregulated, turning the metabolic defect into a therapeutic opportunity

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS20260021132A1Pharmacological therapy for mitochondrial DNA depletion deletions syndrome involving mutations in the GUK1 gene

Publication Date: 2026.01.22 THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK

AI summary

Compositions and methods relating to a pharmacological therapy for a human genetic disease, specifically mitochondrial DNA depletion-deletions syndromes, and more specifically, those related to mutations in the GUK1 gene. The pharmacological therapy involves the administration of deoxyguanosine (dG), a purine nucleoside phosphorylase (PNP) inhibitor, including but not limited to forodesine, or both.