Prime Editing Composition for FXN GAA Repeat Excision

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Solution Overview

Problem

Current therapeutic strategies for Friedreich's ataxia, caused by hyper-expansion of GAA repeats in the FXN gene, are inadequate in restoring sufficient frataxin levels due to epigenetic silencing, leading to neurodegeneration and cardiomyopathy, with no effective method to directly address the GAA repeat expansions.

Innovation Solution

Utilization of prime editing guide RNAs (PEgRNAs) and prime editing compositions to target and edit or excise the GAA repeat expansions in the FXN gene, employing a dual prime editing approach with specific spacers and editing templates to restore normal FXN expression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If current therapeutic strategies are used to restore FXN expression, then frataxin levels are partially improved, but the GAA repeat expansions remain and epigenetic silencing persists

Engineering Contradiction:

Improvefrataxin levelsVSAvoidefficacy of treatment

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent applies the extraction principle by using prime editing to specifically remove the GAA repeat expansions from the FXN gene intron 1. The PEgRNA is designed with a spacer complementary to the GAA repeat sequence, enabling the prime editor to excise these harmful expansions directly from the genome, thereby eliminating the root cause of epigenetic silencing and restoring normal FXN expression.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent replaces conventional therapeutic approaches (which rely on pharmacological or protein replacement therapies) with a genome editing mechanism. By using prime editing technology, the treatment directly modifies the DNA sequence to remove pathogenic expansions, substituting mechanical/genetic intervention for biochemical compensation strategies.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Reliability

If GAA repeat expansions are reduced through prime editing, then FXN transcription is improved, but the complexity of the editing composition increases

Engineering Contradiction:

ImproveFXN transcription restorationVSAvoidediting composition structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent merges multiple functional elements into a single integrated PEgRNA molecule. The PEgRNA combines the spacer (for GAA repeat recognition), the gRNA core (for Cas9 binding and targeting), and the extension arm (containing the editing template and PBS) into one unified structure. This consolidation simplifies delivery and reduces the number of separate components needed compared to traditional CRISPR-Cas9 systems requiring separate donor DNA and guide RNA.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The PEgRNA exhibits multi-functionality by simultaneously performing target recognition (via spacer), gene targeting (via gRNA core), and providing the editing template (via extension arm). This single molecule accomplishes what would traditionally require multiple separate components, reducing overall system complexity while maintaining editing capability.

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Object-affected harmful factors

If dual prime editing is used to excise GAA repeats, then neurodegenerative symptoms are mitigated, but the manufacturing and delivery complexity increases

Engineering Contradiction:

Improveneurodegenerative symptomsVSAvoidcomposition production

Core Design Contradiction:

Object-affected harmful factorsVSEase of manufacture

Solution Approach 1:

The patent uses a copied/adapted version of the PEgRNA structure optimized for dual-strand editing. The PEgRNA design incorporates specific sequence features (spacer length, PBS complementarity, extension arm configuration) that are replicated and adapted for targeting the GAA repeats in both directions, enabling efficient excision while maintaining manufacturability through standardized molecular architecture.

Inventive Principle:

Principle #26Copying

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 dual prime editing method effectively reduces GAA repeat expansions, enhancing frataxin production and mitigating the neurodegenerative and cardiomyopathic symptoms of Friedreich's ataxia by improving mitochondrial function and iron homeostasis.

Implementation Method 1

a first gRNA core capable of binding to a Cas9 protein

Methodology Applied

Scientific EffectProtein-RNA binding:

Implementation Method 2

a first spacer that is complementary to a first search target sequence on a first strand of a FXN gene

Methodology Applied

Scientific EffectNucleic acid hybridization:

Implementation Method 3

dual prime editing as a genome editing approach for treating genetic diseases, for example, the repeat expansion disorder Friedreich's ataxia

Methodology Applied

Scientific EffectDNA cleavage:

Data Source

PatentUS20260071211A1Genome Editing Compositions and Methods for Treatment of Friedreich's Ataxia

Publication Date: 2026.03.12 PRIME MEDICINE INC

AI summary

Provided herein are prime editing methods and compositions for treatment of genetic disorders such as Friedreich ataxia.