Neurturin variants with reduced heparin binding
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Solution Overview
Problem
Current neurturin therapies face limitations due to high affinity for heparan sulfate, which restricts diffusion and efficacy in treating neurological disorders, as seen in clinical trials where neurturin fails to distribute evenly in the brain, suggesting a need for neurturin variants with reduced heparin and heparan sulfate binding affinity while maintaining neurotrophic activity.
Innovation Solution
Development of neurturin polypeptides with specific mutations at amino acids 51 to 63, such as R52A, R56A, and R58A, or R54A, R61A, which reduce heparin binding affinity while retaining the ability to induce RET phosphorylation and maintain neurotrophic activity, allowing broader biodistribution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If neurturin is used to treat neurological disorders, then neurotrophic activity is achieved, but heparin and heparan sulfate binding affinity causes restricted diffusion and uneven distribution in the brain
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues (51-63 region) in the neurturin protein sequence to alter its binding affinity parameters for heparin and heparan sulfate. This modifies the biochemical properties of neurturin to reduce non-specific binding while preserving receptor-mediated neurotrophic signaling, thereby improving brain penetration and distribution without losing therapeutic activity.
2Stability of the object's composition
If neurturin binds tightly to heparin and heparan sulfate, then stability is improved, but diffusion and delivery to target sites are reduced
Solution Approach 1:
The patent applies local quality by making targeted mutations only in the specific amino acid region (51-63) responsible for heparin/heparan sulfate binding, while leaving the rest of the protein structure intact. This localized modification reduces binding affinity at the problematic interface while preserving the overall stability and neurotrophic function of the neurturin molecule through conservation of other critical structural and functional elements.
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 mutated neurturin variants exhibit enhanced biodistribution and retained biological activity, potentially improving treatment outcomes for neurological disorders by ensuring effective delivery and action within the brain and peripheral nervous systems.
Implementation Method 1
neurturin molecules that have reduced heparin, heparan sulfate and heparan sulfated proteoglycan binding ability
Implementation Method 2
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.