Extracellular CES2 Engineering for Obesity and Glucose Control

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Solution Overview

Problem

Metabolic disorders such as obesity and diabetes are challenging due to defects in glucose metabolism and organ dysfunction, leading to increased morbidity and mortality, with existing treatments being inadequate.

Innovation Solution

Enhancing extracellular Carboxylesterase 2 (CES2) activity through administration of CES2 active agents, such as CES2 polypeptides or nucleic acids, to increase systemic CES2 levels, particularly by removing the C-terminal ER localization domain, thereby promoting metabolic disorder treatment.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing treatments for metabolic disorders are used, then treatment coverage is provided, but treatment effectiveness is inadequate

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidtreatment coverage

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies the CES2 protein by removing the C-terminal ER localization domain (amino acids 493-502 in human CES2), which changes the subcellular localization parameter from intracellular (ER-bound) to extracellular. This parameter change enables the enzyme to function in the extracellular space where it can metabolize circulating lipids and improve glucose tolerance, thereby enhancing treatment effectiveness for metabolic disorders while maintaining broad applicability across different metabolic conditions

Inventive Principle:

Principle #35Parameter changes

2Quantity of substance

If CES2 activity is enhanced by removing C-terminal ER localization domain, then extracellular CES2 levels increase, but protein structural complexity changes

Engineering Contradiction:

Improveextracellular CES2 levelsVSAvoidprotein structure

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The patent extracts and removes the C-terminal ER localization domain (amino acids 493-502) from the CES2 protein structure. This extraction eliminates the retention signal that anchors CES2 to the endoplasmic reticulum, allowing the modified protein to be secreted into the extracellular space. The removed segment is relatively small (9 amino acids) compared to the full protein structure, thus increasing extracellular CES2 levels without substantially complicating the overall protein structure

Inventive Principle:

Principle #2Taking out (Extraction)

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 enhanced CES2 activity effectively treats metabolic disorders by reducing obesity, improving glucose tolerance, and enhancing endurance, demonstrating significant anti-obesity and anti-diabetic effects.

Implementation Method 1

enhancing extracellular Carboxylesterase 2 (CES2) activity in the subject to treat the subject for the metabolic disorder

Methodology Applied

Scientific EffectEnzyme: Enzyme

Data Source

PatentUS20260021165A1Extracellular Carboxylesterase 2 (CES2) for the Treatment of Metabolic Disease

Publication Date: 2026.01.22 THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV

AI summary

Methods of treating a metabolic disorder in a subject are provided. Aspects of the method include enhancing extracellular Carboxylesterase 2 (CES2) activity in the subject in order to treat the subject for the metabolic disorder. Also provided are compositions for use in practicing the methods.