Truncated GDNF Variants for Enhanced Brain Penetration

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Solution Overview

Problem

Current GDNF variants face challenges in stability, bio-distribution, and immunogenicity, limiting their effectiveness in treating Parkinson's disease, with wild-type GDNF showing mixed results in clinical trials and limited brain penetration due to heparin and extracellular matrix binding.

Innovation Solution

Development of novel Δ31-N-terminus truncated GDNF variants with specific amino acid substitutions and the use of signal secretion peptides to enhance stability, bio-distribution, and reduce immunogenicity, while maintaining receptor binding and neuroprotective effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If wild-type GDNF is administered to patients with Parkinson's disease, then neuroprotective effects are observed, but clinical improvement is mixed and brain penetration is limited

Engineering Contradiction:

Improveclinical effectivenessVSAvoidheparin and extracellular matrix binding

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent removes the first 31 amino acids (N-terminal region) from the GDNF protein sequence, which are responsible for heparin and extracellular matrix binding. This extraction eliminates the harmful interaction while preserving the neuroprotective domain (amino acids 32-134) that mediates clinical effects.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent modifies the protein structure by deleting specific amino acid residues (positions 1-31) and introducing mutations at positions 84, 88, 90, 125, and 130. These parameter changes in the protein sequence alter binding properties and enhance brain penetration while maintaining therapeutic activity.

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If truncated GDNF proteins are used to improve brain penetration, then delivery is enhanced, but stability and immunogenicity properties deteriorate

Engineering Contradiction:

Improvebrain penetrationVSAvoidprotein stability

Core Design Contradiction:

Object-affected harmful factorsVSStability of the object's composition

Solution Approach 1:

The patent introduces specific amino acid substitutions at positions 84 (K or A), 88 (R or K), 90 (R or K), 125 (K or E), and 130 (R or E) in the truncated GDNF protein. These parameter changes in the protein sequence enhance stability and reduce immunogenicity while maintaining the truncated structure that enables improved brain penetration.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If wild-type GDNF is used, then receptor binding is maintained, but heparin binding causes limited bio-distribution

Engineering Contradiction:

Improvereceptor bindingVSAvoidheparin binding

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and removes the N-terminal 31 amino acids that mediate heparin binding, while preserving the C-terminal domain (amino acids 32-134) that contains the receptor binding site. This selective removal eliminates heparin interaction without compromising GFRα1 receptor binding.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent applies different functional properties to different regions: the truncated N-terminus is optimized for reduced heparin binding and improved bio-distribution, while the C-terminal domain maintains high-affinity receptor binding. This local differentiation of functional properties resolves the contradiction.

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP2696889B1Variants of human gdnf

Publication Date: 2017.11.15 ELI LILLY & CO

AI summary

The present invention relates to novel variants of human glial cell-derived neurotrophic factor (GDNF) and methods for their use.