Stabilized IGF2 Polypeptides for Muscle Regeneration
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Solution Overview
Problem
As individuals age, tissue progenitor cells lose their regenerative potential, leading to challenges in treating aging-related muscle and soft-tissue diseases, disorders, and injuries.
Innovation Solution
The development of polypeptides comprising an IGF2 amino acid sequence and a heterologous polypeptide sequence, which enhance the stability and biological function of IGF2, are used to treat muscle and soft-tissue conditions. These polypeptides include mutations that improve stability by reducing backbone cleavage and blocking peptide backbone cleavage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If IGF2 polypeptide is used to promote tissue regeneration, then regenerative potential is improved, but molecular stability deteriorates due to backbone cleavage
Solution Approach 1:
The patent identifies sites of backbone cleavage as harmful to molecular stability, then strategically introduces mutations at these specific sites to block cleavage. This converts the harmful effect of proteolytic degradation into a beneficial design feature by using the known cleavage sites as targets for stabilizing mutations, thereby preserving the IGF2 polypeptide's regenerative function while enhancing its stability
2Stability of the object's composition
If heterologous polypeptide sequence is added to enhance stability, then molecular stability is improved, but device complexity increases
Solution Approach 1:
The patent merges the IGF2 polypeptide with a heterologous polypeptide sequence to create a fusion protein. This combination achieves two objectives simultaneously: the heterologous portion enhances molecular stability and extends half-life, while the IGF2 portion retains regenerative bioactivity. The merging of these two functional elements resolves the contradiction by integrating stability enhancement without requiring separate delivery systems
3Stability of the object's composition
If mutations are introduced to block backbone cleavage, then molecular stability is improved, but manufacturing precision requirements increase
Solution Approach 1:
The patent applies mutations locally at specific cleavage sites within the IGF2 polypeptide sequence rather than throughout the entire molecule. By targeting only the critical residues susceptible to proteolytic cleavage, the invention achieves stability enhancement with minimal changes to the overall sequence, thereby reducing manufacturing complexity while maintaining high precision where it matters most
Data Source
AI summary
Described herein are polypeptides with an IGF2 amino acid sequence and an amino acid sequence from a heterologous polypeptide for treatment of soft-tissue and muscle diseases, disorders, and injuries. Mutations within the IGF2 amino acid sequence improved stability by reducing backbone cleavage. Synergistic combinations of an Insulin-like Growth Factor 1 Receptor (IGF1R) agonist and a short chain fatty acid are also described. Methods of treating muscle and soft-tissue diseases comprising administering the polypeptides and/or synergistic compositions are provided herein.