Codon-Optimized MRC1 Nucleic Acid for Gaucher Disease Antibody Detection

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Solution Overview

Problem

Patients receiving enzyme replacement therapy for Gaucher disease often develop an immune response, such as neutralizing antibodies, which can reduce the effectiveness of the treatment, necessitating a method to detect and manage these responses effectively.

Innovation Solution

The introduction of a codon-optimized nucleic acid sequence encoding the mannose receptor, C type 1 (MRC1), into cells allows for the detection of neutralizing antibodies by assessing cellular uptake of glucocerebrosidase, enabling the identification of suitable treatment alternatives for patients with Gaucher disease.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a nucleic acid sequence encoding MRC1 is introduced into prokaryotic cells, then the ability to detect neutralizing antibodies is improved, but cell toxicity occurs and sequence inversion results

Engineering Contradiction:

Improvedetection capabilityVSAvoidcell toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The nucleic acid sequence encoding MRC1 was codon-optimized for prokaryotic expression, changing the genetic code parameters to match prokaryotic codon usage preferences. This modification eliminated cell toxicity and sequence inversion while maintaining the ability to detect neutralizing antibodies through MRC1 expression on eukaryotic cells

Inventive Principle:

Principle #35Parameter changes

2Reliability

If enzyme replacement therapy with GCB is administered to patients, then treatment of Gaucher disease is achieved, but immune response including neutralizing antibody production occurs

Engineering Contradiction:

Improvetreatment efficacyVSAvoidimmune response

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent introduces MRC1-expressing eukaryotic cells as an intermediary diagnostic tool. These cells serve as a mediator to detect neutralizing antibodies in patient serum, enabling identification of patients who have developed immune responses to GCB therapy and may benefit from alternative treatments

Inventive Principle:

Principle #24Intermediary (Mediator)

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

This approach enables the detection of neutralizing antibodies and facilitates the selection of appropriate enzyme replacement therapies, such as velaglucerase, thereby improving treatment efficacy and patient outcomes by ensuring effective enzyme uptake and utilization.

Implementation Method 1

codon optimization of at least a portion of the nucleic acid sequence encoding MRC1 allows for normal plasmid amplification in prokaryotic cells and stable expression of MRC1 on the surface of cells eukaryotic cells

Methodology Applied

Scientific EffectCodon optimization:

Implementation Method 2

assessing cellular uptake of glucocerebrosidase, enabling the identification of suitable treatment alternatives for patients with Gaucher disease

Methodology Applied

Scientific EffectReceptor-mediated uptake:

Data Source

PatentEP2595651B1Mannose receptor c type 1 (MRC1) codon optimized cell line and uses thereof

Publication Date: 2017.03.29 SHIRE HUMAN GENETIC THERAPIES INC

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AI summary

Described herein are isolated nucleic acid molecules comprising nucleotide sequence encoding mannose receptor, C type 1 (MRCl) wherein the 5' region of the nucleotide sequence encoding MRCl is codon optimized; cells comprising such nucleic acid molecules; and methods of detecting antibody production, e.g., neutralizing antibody production, in a subject being treated for Gaucher disease using such cells.