GalNAc-Conjugated ASO for G6PC mRNA Splicing Correction
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Solution Overview
Problem
Glycogen storage disease type Ia patients with the c.648G>T mutation in the G6PC gene face challenges due to abnormal splicing of mRNA, leading to defective G6PC enzyme production, resulting in hypoglycemia, liver enlargement, and increased risk of hepatic adenoma, for which current therapies are inadequate.
Innovation Solution
An antisense oligonucleotide (ASO) is administered to correct the abnormal splicing of mRNA in the G6PC gene, specifically targeting the c.648G>T mutation, allowing for the production of functional G6PC protein, thereby reducing the risk of hypoglycemic episodes and hepatic adenoma progression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotide is administered to correct abnormal splicing, then G6PC protein production is normalized, but delivery efficiency to hepatic parenchymal cells remains challenging
Solution Approach 1:
The patent uses asialoglycoprotein receptor (ASGPR) as an intermediary mediator to facilitate oligonucleotide delivery to hepatic parenchymal cells. The ASGPR naturally present on liver cell surfaces binds to the oligonucleotide conjugate, enabling targeted delivery without requiring complex external delivery systems. This resolves the contradiction by providing reliable gene correction through a biologically-mediated delivery mechanism rather than complex engineering solutions.
2Productivity
If GalNAc conjugate is used for oligonucleotide delivery, then hepatocellular uptake is enhanced, but the complexity of drug formulation increases
Solution Approach 1:
The patent modifies the oligonucleotide by conjugating it with N-acetyl-D-galactosamine (GalNAc) molecules, changing the chemical parameters of the drug molecule to enable recognition by ASGPR. This single chemical modification dramatically enhances hepatocellular uptake efficiency while maintaining relatively simple formulation requirements, as the GalNAc-conjugated oligonucleotide can be administered as a straightforward pharmaceutical composition without complex delivery vehicle requirements.
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 ASO effectively repairs the G6PC gene at the mRNA level, normalizing G6PC protein production, which in turn addresses hypoglycemia, liver swelling, and reduces the risk of hepatic adenoma in glycogen storage disease type Ia patients.
Implementation Method 1
an antisense oligonucleotide (ASO) is administered to correct the abnormal splicing of mRNA in the G6PC gene, specifically targeting the c.648G>T mutation
Data Source
AI summary
The present invention establishes a molecular therapy for glycogen storage disease type Ia. The present invention provides an oligonucleotide of 15-30 bases comprising a nucleotide sequence complementary to die cDNA of G6PC gene with c.648G>T mutation, wherein the oligonucleotide comprises a sequence complementary to a region comprising any site between the 82nd to the 92nd nucleotide from the 5′ end of exon 5 of the G6PC gene with c.648C>T mutation, a pharmacologically acceptable salt or solvate thereof. Also provided is a pharmaceutical drug comprising the oligonucleotide, a pharmacologically acceptable salt or solvate thereof (e.g., therapeutic drug for glycogen storage disease type Ia).