Modified EKLF Polypeptide for ALS Treatment

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Solution Overview

Problem

Current treatments for amyotrophic lateral sclerosis (ALS) only slow the progression of symptoms and do not reverse the damage, with no available cure.

Innovation Solution

Administration of a modified Erythroid Kruppel-like factor (EKLF) polypeptide with reduced sumoylation, or modified bone marrow cells containing the modified EKLF gene, to subjects to treat or prevent ALS.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If current FDA-approved treatments (Riluzole or Edaravone) are administered to ALS patients, then the progression of ALS symptoms is slowed, but the treatments cannot reverse the damage and only extend life expectancy by limited periods

Engineering Contradiction:

Improvelife expectancy extensionVSAvoidcurative effectiveness

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The invention modifies the EKLF polypeptide by changing a specific amino acid residue (lysine to arginine substitution at position 74 in mice or position 54 in humans), which alters the sumoylation status of the protein. This parameter change in the polypeptide structure leads to reduced sumoylation and subsequently restores SOD1 function, providing a curative effect rather than just symptomatic relief.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If wild-type EKLF polypeptide is expressed in ALS models, then SOD1 function is suppressed, but expressing modified EKLF with reduced sumoylation restores SOD1 function and reverses neurodegeneration

Engineering Contradiction:

ImproveSOD1 function restorationVSAvoidpolypeptide modification complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention applies local quality modification by changing only a single amino acid residue in the EKLF polypeptide sequence. This localized change at a specific position (affecting the sumoylation site) is sufficient to alter the global function of the protein by reducing sumoylation, thereby restoring SOD1 function without needing to modify the entire polypeptide structure.

Inventive Principle:

Principle #3Local quality

3Reliability

If bone marrow cells are modified to express modified EKLF and transplanted into ALS subjects, then exercise ability and learning memory are improved, but the treatment complexity and administration procedure are increased

Engineering Contradiction:

Improveneurodegeneration reversalVSAvoidtreatment procedure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention uses modified bone marrow cells as an intermediary vehicle to deliver the modified EKLF polypeptide to the central nervous system. The bone marrow cells are engineered to express the modified EKLF and then transplanted into ALS subjects, where they serve as a source of the therapeutic polypeptide that can cross the blood-brain barrier and exert neuroprotective effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250099538A1Methods of treating neurodegenerative diseases

Publication Date: 2025.03.27 ACAD SINICA

AI summary

Disclosed herein are methods of preventing or treating ALS by use of a modified EKLF polypeptide, a modified nucleic acid encoding the modified EKLF polypeptide, or modified bone marrow cells comprising the modified nucleic acid. According to embodiments of the present disclosure, the modified EKLF polypeptide comprises an amino acid modification that confers reduced sumoylation in a wild-type EKLF polypeptide.