TAT-FXN Fusion Polypeptide Sequence Changes for High-Concentration Dosing

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Solution Overview

Problem

Current treatments for Friedreich's Ataxia (FRDA) are limited by the poor solubility of Transactivator of Transcription-frataxin (TAT-FXN) fusion polypeptides at physiological pH, restricting their concentration in pharmaceutical compositions and dosage.

Innovation Solution

Development of a new TAT-FXN fusion polypeptide with enhanced solubility, allowing concentrations greater than 50 mg/mL, and formulations suitable for subcutaneous injection.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If the TAT-FXN fusion polypeptide is used to treat Friedreich's Ataxia, then therapeutic efficacy is improved, but solubility at physiological pH deteriorates

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidsolubility

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent modifies the amino acid sequence of the TAT-FXN fusion polypeptide by substituting specific residues (e.g., replacing hydrophobic residues with hydrophilic ones) to change its solubility parameters while preserving its cell-penetrating and frataxin-delivery functions. This allows the polypeptide to maintain therapeutic efficacy at physiological pH while achieving significantly improved solubility.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a modified composite polypeptide structure that combines the cell-penetrating TAT domain with the frataxin (FXN) domain, but with engineered modifications to the TAT sequence that enhance overall solubility. The modified TAT-FXN fusion polypeptide acts as a composite material with optimized properties for both delivery function and solubility.

Inventive Principle:

Principle #40Composite materials

2Quantity of substance

If the concentration of TAT-FXN fusion polypeptide is increased to improve dosage, then therapeutic effect is enhanced, but precipitation occurs

Engineering Contradiction:

Improvedosage concentrationVSAvoidprecipitation

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

By modifying the amino acid composition of the TAT domain in the fusion polypeptide, the patent changes the physical-chemical parameters of the molecule to increase its solubility product. This allows the formulation to achieve high concentrations (greater than 50 mg/mL) without precipitation, enabling significantly higher dosages to be administered.

Inventive Principle:

Principle #35Parameter changes

3Stability of the object's composition

If the solubility of TAT-FXN fusion polypeptide is improved, then dosage concentration can be increased, but the amino acid sequence must be modified

Engineering Contradiction:

ImprovesolubilityVSAvoidamino acid sequence complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent applies local quality modification by making targeted amino acid substitutions only in specific regions of the TAT domain rather than redesigning the entire polypeptide sequence. This localized modification approach improves solubility while minimizing changes to the overall structure and preserving the essential functions of both TAT and FXN domains.

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP4004022B1Materials and methods for treating friedreich's ataxia

Publication Date: 2025.12.31 THE TRUSTEES OF INDIANA UNIV

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AI summary

A TAT-FXN fusion polypeptide useful in treating subjects diagnosed with Friedrich's Ataxia, hypertrophic cardiomyopathy, or both are disclosed, as are related methods of treatment and pharmaceutical compositions.