Optimized PAH Gene Expression Cassette for PKU Treatment

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Solution Overview

Problem

Current treatments for phenylketonuria (PKU) in adults are inadequate, leading to high peripheral blood phenylalanine levels, neurological symptoms, and quality of life issues, with existing gene therapies posing risks of liver toxicity at high doses.

Innovation Solution

An optimized PAH gene and expression cassette, including a polynucleotide molecule and viral vector, for stable and effective expression of human PAH in the liver at lower doses, using an adeno-associated virus vector to maintain low phenylalanine levels.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If high doses of existing gene therapy are used to treat PKU, then phenylalanine levels can be reduced, but liver toxicity occurs

Engineering Contradiction:

Improvephenylalanine reductionVSAvoidliver toxicity

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent optimizes the PAH gene expression cassette parameters including promoter selection (liver-specific promoters like ALB, AAT), enhancer elements (ApoE HCR, CMV), and codon optimization to achieve high-level PAH expression at lower viral doses, thereby reducing liver toxicity while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses adeno-associated virus (AAV) vectors as intermediaries to deliver the optimized PAH gene expression cassette to liver cells, enabling sustained PAH protein production without the direct toxic effects of high-dose gene therapy

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If existing gene therapy approaches are used, then PAH expression can be achieved, but the treatment is not durable and stable

Engineering Contradiction:

ImprovePAH expression effectivenessVSAvoidtreatment durability

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent designs the expression cassette with liver-specific promoters and enhancers that ensure continuous and sustained PAH gene expression in hepatocytes over long periods, achieving durable therapeutic effect without requiring repeated administrations

Inventive Principle:

Principle #20Continuity of useful action

Solution Approach 2:

The optimized PAH gene expression cassette is designed to be self-sufficient with all necessary regulatory elements (promoter, enhancer, polyA signal) integrated, enabling autonomous and stable PAH protein production in the liver without external intervention

Inventive Principle:

Principle #25Self-service

3Quantity of substance

If oral medications are used for adult PKU patients, then phenylalanine levels can be controlled, but immune-related side effects occur and onset is slow

Engineering Contradiction:

Improvephenylalanine controlVSAvoidtreatment safety and speed

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent replaces the mechanical/enzymatic approach of oral medications (tetrahydrobiopterin, pegvaliase) with a genetic approach using AAV-delivered PAH gene therapy, which directly restores endogenous PAH enzyme production, providing faster onset and avoiding immune-related side effects of long-term medication

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentEP4613863A1Optimized PAH gene and expression cassette and use thereof

Publication Date: 2025.09.10 SUZHOU NGGT BIOTECHNOLOGY CO LTD

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AI summary

The present disclosure relates to an optimized PAH gene and an expression cassette and use thereof. Specifically, a polynucleotide molecule encoding PAH protein is disclosed. By means of using the polynucleotide molecule, expression cassette, expression vector, virion, and/or pharmaceutical composition provided herein, human PAH can be effectively, persistently, and stably expressed in the liver at a relatively low dose, thus steadily keeping the blood phenylalanine concentration in a subject at a relatively low level for a long period. Therefore, the present disclosure can be used for the treatment of phenylketonuria.