Modified-Intron UGT1A1 Constructs for AAV Hyperbilirubinemia Therapy

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Solution Overview

Problem

Current therapies for Crigler-Najjar syndrome (CN) and Gilbert's syndrome, such as phototherapy and liver transplantation, are inadequate due to inefficiencies, compliance issues, and potential complications, while gene-based therapies using AAV vectors have room for improvement in efficacy.

Innovation Solution

A codon-optimized UGT1A1 coding sequence with increased GC content and modified introns, specifically optimized HBB2 introns, is integrated into an expression cassette within AAV vectors to enhance protein expression and reduce immunogenicity, targeting liver cells for effective bilirubin metabolism.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If phototherapy is used to treat Crigler-Najjar syndrome, then bilirubin levels can be controlled, but patient compliance is poor and therapy must be carried on for 10-12 hours each day

Engineering Contradiction:

Improvebilirubin level controlVSAvoidpatient compliance

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent applies preliminary action by delivering a functional UGT1A1 gene copy in advance via AAV vector, enabling the liver to produce the deficient enzyme endogenously. This one-time gene delivery establishes long-term therapeutic effect without requiring daily phototherapy sessions, thereby improving patient compliance while maintaining reliable bilirubin control

Inventive Principle:

Principle #10Preliminary action

2Reliability

If phototherapy is used to treat Crigler-Najjar syndrome, then bilirubin levels can be controlled, but loss of efficacy occurs during growth

Engineering Contradiction:

Improvebilirubin level controlVSAvoidtherapy duration

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The gene therapy approach delivers a stable functional UGT1A1 gene that integrates into the patient's genome and continues to produce enzyme throughout growth and development. This preliminary genetic correction provides durable, long-term efficacy that persists through childhood and adulthood, overcoming the limitation of phototherapy which requires continuous administration

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The corrected UGT1A1 gene enables the patient's own liver cells to self-produce the functional enzyme needed for bilirubin metabolism. This self-service mechanism eliminates dependency on external phototherapy and provides sustained therapeutic effect throughout the patient's lifetime

Inventive Principle:

Principle #25Self-service

3Reliability

If standard UGT1A1 coding sequence is used in AAV vectors, then gene therapy can be delivered, but immunogenicity is increased

Engineering Contradiction:

Improvegene therapy deliveryVSAvoidimmune response

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by codon-optimizing the UGT1A1 coding sequence to increase GC content and modify nucleotide composition while preserving the amino acid sequence. This biochemical parameter optimization reduces the recognition of foreign DNA by the immune system, thereby decreasing immunogenicity while maintaining effective gene delivery and expression

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3546585B1Nucleic acids comprising a modified intron for use in the treatment of hyperbilirubinemia

Publication Date: 2025.09.10 GENETHON

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AI summary

The invention relates to a nucleic acid sequence useful in the treatment of hyperbilirubinemia, in particular in the treatment of Crigler-Najjar syndrome. More particularly, the nucleic acid sequence of the present invention is a codon-optimized UGT1A1 coding sequence.