TAT-FXN Fusion Polypeptide Composition for High-pH Solubility
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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 therapeutic efficacy.
Innovation Solution
Development of a new TAT-FXN fusion polypeptide with enhanced solubility, allowing for concentrations greater than 50 mg/mL in aqueous solutions, enabling higher dose administration through compositions suitable for subcutaneous injection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the TAT-FXN fusion polypeptide is used for treating Friedreich's Ataxia, then therapeutic efficacy is improved, but solubility at physiological pH deteriorates
Solution Approach 1:
The patent modifies the amino acid sequence of the TAT-FXN fusion polypeptide by substituting specific residues (e.g., replacing hydrophobic amino acids with hydrophilic ones at strategic positions) to alter its solubility parameters while preserving its therapeutic function. This allows the polypeptide to maintain both efficacy and solubility at physiological pH
Solution Approach 2:
The invention creates a modified composite polypeptide structure that combines the cell-penetrating TAT domain with the frataxin domain, while incorporating solubility-enhancing elements such as additional charged residues or solubility tags, resulting in a fusion protein with improved overall solubility properties without losing therapeutic activity
2Quantity of substance
If concentration of TAT-FXN fusion polypeptide is increased to achieve higher doses, then therapeutic effectiveness is improved, but precipitation occurs
Solution Approach 1:
By changing the amino acid composition to include more hydrophilic residues and optimizing the charge distribution throughout the polypeptide structure, the modified fusion protein maintains solubility at high concentrations (greater than 50 mg/mL), preventing precipitation while enabling higher dose formulations
Solution Approach 2:
The patent applies local modifications at specific regions of the polypeptide chain, particularly at interfaces prone to aggregation and at the N- and C-termini, to enhance solubility locally without affecting the overall therapeutic function, allowing high-concentration stable formulations
Data Source
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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.