ARG1 mRNA Therapy With Nucleotide Modification for Arginase Deficiency

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Solution Overview

Problem

Current treatments for arginase deficiency (AD) are inadequate, failing to effectively reduce toxic ammonia and arginine levels, and there is a need for improved therapeutic options.

Innovation Solution

Intracellular delivery of mRNA encoding arginase 1 (ARG1) polypeptide using modified nucleotides to minimize immune response and optimize translation efficiency, combined with a lipid nanoparticle delivery system for enhanced cellular uptake and reduced immunogenicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If mRNA encoding ARG1 is delivered to cells, then ARG1 activity increases and toxic metabolite levels decrease, but immune response is activated and translation efficiency is reduced

Engineering Contradiction:

ImproveARG1 activityVSAvoidimmune response

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies nucleotide parameters within the mRNA molecule, specifically incorporating pseudouridine and other modified nucleotides at controlled frequencies (e.g., 5-50% of total nucleotides). This parameter change reduces immune system recognition while maintaining or enhancing translation efficiency, thereby resolving the contradiction between therapeutic efficacy and immune activation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite mRNA structure combining modified nucleotides (pseudouridine, 5-methylcytidine, etc.) with standard nucleotides in specific ratios and positions. This composite approach optimizes both immune evasion and translational efficiency, allowing the mRNA to achieve high ARG1 expression without triggering unwanted immune responses

Inventive Principle:

Principle #40Composite materials

2Reliability

If mRNA encoding ARG1 is delivered to cells, then ARG1 activity increases and toxic metabolite levels decrease, but translation efficiency is reduced

Engineering Contradiction:

ImproveARG1 activityVSAvoidtranslation efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent optimizes nucleotide modification parameters to balance immune response reduction with translation efficiency maintenance. By controlling the type, frequency, and distribution of modified nucleotides (e.g., using N1-methylpseudouridine at 10-30% frequency), the mRNA achieves both high stability and efficient translation into ARG1 protein

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses codon optimization strategies that create optimized copies of the ARG1 coding sequence. These copied sequences use preferred codons for human translation machinery while incorporating modified nucleotides, thereby enhancing translation efficiency without compromising the encoded protein function

Inventive Principle:

Principle #26Copying

3Object-affected harmful factors

If conventional treatments are used to reduce ammonia and arginine levels, then some symptomatic relief is achieved, but therapeutic effectiveness is insufficient

Engineering Contradiction:

Improveammonia and arginine levelsVSAvoidtherapeutic effectiveness

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent employs mRNA therapy that enables patient cells to self-produce functional ARG1 enzyme. Rather than externally administering ammonia scavengers or arginine restrictors, the modified mRNA directs cellular machinery to synthesize the deficient enzyme, restoring endogenous metabolic capability and achieving sustained therapeutic effect without continuous external intervention

Inventive Principle:

Principle #25Self-service

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 mRNA therapeutic approach significantly increases ARG1 activity, reduces ammonia, arginine, and orotic acid levels, and enhances glutamine and ornithine levels, providing sustained therapeutic effects for up to 120 hours.

Implementation Method 1

delivery of mRNA encoding an ARG1 polypeptide via a lipid nanoparticle (LNP) delivery system... cellular uptake, intracellular transport and/or endosomal release or endosomal escape

Methodology Applied

Scientific EffectEndocytosis:

Implementation Method 2

The instant invention features the incorporation of modified nucleotides within therapeutic mRNAs to (1) minimize unwanted immune activation (e.g., the innate immune response associated with the in vivo introduction of foreign nucleic acids)

Methodology Applied

Scientific EffectInnate immune response modulation:

Implementation Method 3

The mRNA therapeutics of the invention are particularly well-suited for the treatment of AD as the technology provides for the intracellular delivery of mRNA encoding a arginase 1 (ARG1) polypeptide followed by de novo synthesis of functional ARG1 polypeptide within target cells

Methodology Applied

Scientific EffectTranslation:

Implementation Method 4

ARG1's biological function is to catalyze the hydrolysis of arginine to ornithine and urea

Methodology Applied

Scientific EffectHydrolysis: Hydrolysis

Data Source

PatentUS20260000792A1Polynucleotides encoding arginase 1 for the treatment of arginase deficiency

Publication Date: 2026.01.01 MODERNATX INC

AI summary

This disclosure relates to mRNA therapy for the treatment of arginase deficiency (AD). mRNAs for use in the invention, when administered in vivo, encode arginase 1 (ARG1). mRNA therapies of the disclosure increase and/or restore deficient levels of ARG1 expression and/or activity in subjects. mRNA therapies of the disclosure further decrease abnormal accumulation of ammonia associated with deficient ARG1 activity in subjects.