FKRP Polynucleotide Sequence Changes for Higher Gene Expression

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Solution Overview

Problem

Current gene therapy approaches for treating FKRP deficiencies, such as Limb-Girdle Muscular Dystrophy type 2I (LGMD2I), do not achieve sufficient expression levels of the FKRP protein, limiting their therapeutic efficacy.

Innovation Solution

A modified polynucleotide encoding human FKRP is developed, optimized to suppress frameshift start codons, thereby enhancing FKRP expression when delivered via an AAV9 vector, ensuring higher levels of FKRP protein production.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current gene therapy approaches are used to deliver FKRP encoding polynucleotides, then therapeutic treatment is provided, but the expression level of FKRP protein remains insufficient

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidFKRP expression level

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent modifies the polynucleotide sequence by introducing specific mutations that eliminate frameshift start codons (ATG sequences) within the coding region. This parameter change in the nucleotide sequence prevents alternative reading frames and ensures proper translation initiation, thereby increasing FKRP protein expression levels while maintaining therapeutic function

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs AAV9 viral vectors as a delivery mechanism to transport the optimized polynucleotide to target cells. The viral vector system efficiently transduces cells and enables sustained expression of the FKRP protein, overcoming the limitation of insufficient protein production from conventional delivery methods

Inventive Principle:

Principle #29Pneumatics and hydraulics

2Adaptability or versatility

If frameshift start codons are present in the polynucleotide sequence, then multiple transcript variants are generated, but FKRP expression efficiency decreases

Engineering Contradiction:

Improvetranscript varietyVSAvoidFKRP expression efficiency

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent specifically identifies and removes frameshift start codons (ATG sequences) from the polynucleotide coding region. By extracting these problematic sequences, the invention eliminates the generation of alternative transcript variants that would otherwise compete for translation resources and reduce overall FKRP expression efficiency

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent converts the potential harm of having multiple start codons (which causes expression inefficiency) into a benefit by strategically designing the polynucleotide sequence to have a single optimized start codon. This controlled initiation site ensures efficient translation and high levels of functional FKRP protein production

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS12582723B2Polynucleotides encoding a human FKRP protein

Publication Date: 2026.03.24 GENETHON

AI summary

The present invention concerns synthetic polynucleotides encoding a human fukutin-related protein (FKRP) wherein the synthetic polynucleotides contain at least a mutation avoiding supplementary transcript(s) generated from frameshift start codon(s). The synthetic polynucleotides are useful, especially for treating a pathology linked to a FKRP deficiency or induced by a defect in α-dystroglycan (α-DG) glycosylation, such as LGMD2I.