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 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 administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the TAT-FXN fusion polypeptide is used as a therapeutic for FRDA, then therapeutic efficacy is improved, but solubility at physiological pH deteriorates
Solution Approach 1:
The patent modifies the amino acid sequence parameters of the TAT-FXN fusion polypeptide by incorporating specific residues (such as alanine, glycine, serine, or cysteine) at defined positions to alter the solubility characteristics. These sequence parameter changes enable the polypeptide to maintain high solubility at physiological pH while preserving its therapeutic activity, directly resolving the contradiction between efficacy and solubility.
Solution Approach 2:
The patent creates a composite polypeptide structure by fusing the TAT peptide with the FXN protein sequence, forming a chimeric TAT-FXN fusion polypeptide. This composite structure combines the cell-penetrating properties of TAT with the functional properties of frataxin, achieving both therapeutic efficacy and improved solubility through the synergistic interaction of the two peptide components.
2Quantity of substance
If the concentration of TAT-FXN fusion polypeptide in pharmaceutical composition is increased, then dosage is improved, but solubility deteriorates
Solution Approach 1:
The patent changes the chemical parameters of the polypeptide by incorporating specific amino acid residues that enhance solubility. These parameter modifications allow the TAT-FXN fusion polypeptide to remain dissolved at high concentrations (greater than 50 mg/mL) in aqueous formulations at physiological pH, enabling increased dosage without precipitation or loss of solubility.
Data Source
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.