Mutant hIAPP Polypeptides Neutral pH Solubility
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Solution Overview
Problem
Current treatments for diabetes, particularly type 1 and type 2, face challenges due to the aggregation and toxicity of human islet amyloid polypeptide (hIAPP), which limits its solubility and effectiveness when co-formulated with insulin at neutral pH, leading to increased costs and reduced patient compliance.
Innovation Solution
Development of mutant-hIAPP polypeptides with specific amino acid substitutions, such as H18R, G24P, and I26P, that are soluble at neutral pH, non-toxic, and do not form amyloid fibrils, allowing for co-formulation with insulin at neutral pH for improved therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If hIAPP is used as a therapeutic agent, then it can complement insulin effects in glycemic control, but it aggregates and forms toxic amyloid fibrils
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of hIAPP through specific substitutions (e.g., G24P, I26P, S28P, S29P) to alter its physical and chemical properties. These sequence modifications prevent amyloid fibril formation while preserving the peptide's ability to complement insulin's glycemic control effects, thereby resolving the contradiction between therapeutic efficacy and harmful aggregation.
2Stability of the object's composition
If pramlintide is used to improve solubility, then it reduces amyloid formation, but it is not soluble at physiological pH
Solution Approach 1:
The patent employs parameter changes by introducing specific amino acid substitutions at positions 24-29 of the hIAPP sequence. These modifications simultaneously enhance solubility at physiological pH and prevent amyloid formation, overcoming the limitations of pramlintide which requires acidic pH for solubility. The mutated sequence maintains stability and prevents aggregation while achieving neutral pH solubility.
3Adaptability or versatility
If hIAPP and pramlintide are co-formulated, then therapeutic coverage is expanded, but formulation complexity increases due to pH requirements
Solution Approach 1:
The patent applies the merging principle by developing a single formulation system that combines hIAPP and insulin at neutral pH, eliminating the need for separate acidic and neutral formulations. This unified approach expands therapeutic coverage while reducing formulation complexity, as the mutated hIAPP remains stable and soluble at the same pH conditions as modern insulin formulations.
4Reliability
If separate injections are used for pramlintide and insulin, then compatibility is maintained, but cost and patient compliance decrease
Solution Approach 1:
The patent applies merging by creating a single injectable formulation that combines the mutated hIAPP with insulin at neutral pH. This eliminates the need for separate injections, reducing the number of administrations required by patients, lowering costs through reduced medication management, and improving compliance while maintaining formulation compatibility through careful pH control and stability optimization.
Data Source
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Figure 2A~2C
Figure 2D~2G
AI summary
The present disclosure provides for isolated non-naturally occurring, mutant-human IAPP polypeptides. These polypeptides can be formulated or co-formulated at physiological pH, which enable the polypeptides of the instant disclosure to be delivered to a subject having an amyloid-based disease in a single injection with an insulin agent. The present disclosure also provides methods and compositions for treating amyloid-based disease in a subject in need thereof, comprising administering an effective amount of an isolated, mutant-hIAPP polypeptide, including formulations or co-formulations thereof.