CPP-TP Conjugates for MNGIE Thymidine Reduction

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Solution Overview

Problem

Current treatment options for Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) are limited, with stem cell transplantation and liver transplantation associated with high mortality rates, and no general solution available, leading to primarily supportive care for managing symptoms.

Innovation Solution

Development of compounds comprising a cell-penetrating peptide (CPP) moiety coupled to thymidine phosphorylase (TP) or an active fragment/analog thereof, designed to traverse cell membranes and reduce toxic thymidine levels in MNGIE patients.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If stem cell transplantation or liver transplantation is performed to treat MNGIE, then some therapeutic effect may be achieved, but mortality rate increases significantly

Engineering Contradiction:

Improvetherapeutic effectVSAvoidmortality rate

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and addresses the root cause of MNGIE by delivering thymidine phosphorylase enzyme directly to target cells to degrade accumulated thymidine, rather than performing complex transplantation procedures. This extracts the essential therapeutic function (thymidine degradation) from the harmful transplantation approach.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent uses cell-penetrating peptides as intermediaries to deliver thymidine phosphorylase into cells. This intermediary approach enables safe and effective enzyme delivery without the high mortality risks associated with stem cell or liver transplantation.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of operation

If conventional treatment approaches are used for MNGIE, then some symptom management is provided, but no general solution is available

Engineering Contradiction:

Improvesupportive careVSAvoidgeneral solution

Core Design Contradiction:

Ease of operationVSAdaptability or versatility

Solution Approach 1:

The patent creates a universal therapeutic approach that addresses the underlying cause of MNGIE (thymidine accumulation) through a generalizable enzyme delivery system. The cell-penetrating peptide-thymidine phosphorylase conjugate can be applied broadly to treat MNGIE patients regardless of specific symptom presentation, providing both universality and adaptability.

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If thymidine phosphorylase is delivered without cell-penetrating capability, then enzymatic activity is maintained, but cellular uptake is insufficient

Engineering Contradiction:

Improveenzymatic activityVSAvoidcellular uptake

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent merges two distinct functional components: cell-penetrating peptides (which enable cellular uptake) and thymidine phosphorylase (which provides enzymatic activity). The resulting conjugate simultaneously achieves both cellular internalization and thymidine degradation functions that were previously separate.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The patent creates a composite therapeutic molecule combining the cell-penetrating peptide moiety with the thymidine phosphorylase enzyme. This composite structure integrates the membrane-trans穿透 capability of CPPs with the catalytic function of TP, enabling both efficient cellular uptake and maintained enzymatic activity.

Inventive Principle:

Principle #40Composite materials

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 compounds effectively penetrate cells and maintain enzymatic activity, reducing extracellular and intracellular thymidine levels, thereby potentially alleviating the severe digestive and neurological symptoms associated with MNGIE.

Implementation Method 1

compounds comprising a cell-penetrating peptide (CPP) moiety coupled to thymidine phosphorylase (TP) or an active fragment/analog thereof, designed to traverse cell membranes

Methodology Applied

Scientific EffectCell membrane penetration:

Implementation Method 2

thymidine phosphorylase (TP) or an active fragment/analog thereof, designed to traverse cell membranes and reduce toxic thymidine levels

Methodology Applied

Scientific EffectEnzymatic degradation: Enzyme

Data Source

PatentUS20250115885A1Compositions and methods for treating mitochondrial neurogastrointestinal encephalopathy

Publication Date: 2025.04.10 ENTRADA THERAPEUTICS INC

AI summary

Disclosed herein are compositions and methods of treating disclosure provides for compounds for use in treating Mitochondrial Neurogastrointestinal Encephalopathy Syndrome (MNGIE). In some embodiments, the compounds have cell penetrating activity and thymidine phosphorylase activity. In certain embodiments, the compounds disclosed herein comprise: a) at least one cell-penetrating peptide (CPP) moiety; and b) a thymidine phosphorylase, or an active fragment or analog thereof (TP), wherein the CPP is coupled, directly or indirectly, to TP.