Neurturin Polypeptides with Reduced Heparan Sulfate Binding
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Solution Overview
Problem
Current neurturin therapies face limitations due to high affinity for heparan sulfate, which restricts biodistribution and efficacy, particularly in treating neurological disorders, as evidenced by mixed results from previous studies and the failure of neurturin in clinical trials for Parkinson's disease.
Innovation Solution
Development of neurturin polypeptides with reduced heparin and heparan sulfate binding affinity, specifically through mutations in amino acids 51 to 63, that retain neurotrophic activity and ability to induce RET phosphorylation, allowing broader tissue distribution while maintaining biological function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If neurturin is used to treat neurological disorders, then neurotrophic activity is achieved, but binding affinity to heparan sulfate restricts biodistribution and efficacy
Solution Approach 1:
The patent modifies the amino acid sequence of neurturin by introducing mutations at specific positions (e.g., R52A, R56A, R58A, R61A, R63A) to change the binding parameters to heparan sulfate while preserving the receptor binding parameters, thereby achieving reduced affinity for heparan sulfate without compromising neurotrophic activity
Solution Approach 2:
The patent applies local mutations at specific amino acid positions (51-63 region) that are responsible for heparan sulfate binding, while leaving the rest of the protein structure intact and functional, thus locally altering the binding characteristics without affecting overall protein function
2Stability of the object's composition
If neurturin binds to heparan sulfate with high affinity, then stability is improved, but tissue distribution is limited
Solution Approach 1:
The patent changes the binding affinity parameter to heparan sulfate by introducing specific mutations in the amino acid sequence, reducing the binding strength to achieve broader tissue distribution while maintaining stability through other binding mechanisms
3Productivity
If neurturin is administered for Parkinson's disease treatment, then dopamine turnover is stimulated, but clinical trial results were mixed and treatment failed
Solution Approach 1:
The patent modifies the pharmacokinetic parameters of neurturin by reducing heparan sulfate binding affinity, which may improve brain penetration and delivery to target areas, potentially resolving the failure in clinical trials while maintaining the ability to stimulate dopamine turnover
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified neurturin polypeptides exhibit enhanced biodistribution and retained neurotrophic activity, potentially improving treatment outcomes for various neurological disorders by reducing heparan sulfate binding affinity without compromising biological function.
Implementation Method 1
neurturin molecules that have reduced heparin, heparan sulfate and heparan sulfated proteoglycan binding ability
Implementation Method 2
retain the ability to induce phosphorylation of the RET protein upon binding the receptor complex
Data Source
AI summary
Neurturin polypeptides which possess reduced heparin and heparan sulfate binding affinity but retain neurotrophic activity, nucleic acids which encode the neurturin variants and vectors and host cells which express the enhanced neurturin polypeptides. Use of the enhanced neurturin polypeptides, nucleic acids and host cells in the treatment or prevention of disease.