Anti-Transferrin Receptor PMO Conjugates for DMD Exon 52 Skipping

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Solution Overview

Problem

There is no FDA-approved exon skipping therapy for Duchenne Muscular Dystrophy (DMD) patients amenable to exon 52 skipping, affecting approximately 4% of the patient population, despite the potential benefits of antisense oligonucleotides for other exons like 51 and 53.

Innovation Solution

Development of phosphorodiamidate morpholino oligonucleotide (PMO) conjugates comprising an anti-transferrin receptor antibody or its antigen binding fragment, conjugated to a PMO molecule that hybridizes to the DMD gene pre-mRNA transcript to induce exon 52 skipping, generating a mRNA transcript encoding a truncated dystrophin protein.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If antisense oligonucleotides are used to induce exon skipping, then functional dystrophin protein can be produced, but there is no FDA-approved therapy for exon 52 skipping specifically

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidapplicability to exon 52

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent designs PMO molecules with specific sequences tailored to hybridize to exon 52 of the DMD pre-mRNA transcript. The PMO sequence is locally optimized to bind exon 52 with high affinity and specificity, inducing skipping of this particular exon while preserving the therapeutic approach for other exon targets through the same conjugate platform

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The anti-transferrin receptor antibody component provides universal targeting capability to muscle cells, while the PMO molecule provides the specific exon-skipping function. This modular design allows the same antibody-PMO conjugate platform to be adapted for different exon targets by simply changing the PMO sequence, making the system universally applicable to various DMD mutations

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Adaptability or versatility

If antibody-oligonucleotide conjugates are developed for exon 52 skipping, then therapeutic options expand for 4% of DMD patients, but no FDA-approved therapy currently exists for this population

Engineering Contradiction:

Improvepatient population coverageVSAvoidregulatory approval status

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent optimizes multiple parameters of the PMO-antibody conjugate including PMO sequence length (15-30 nucleotides), PMO sequence composition, antibody isotype, and conjugate stoichiometry to achieve effective exon 52 skipping. These parameter optimizations are designed to meet regulatory standards for safety and efficacy while expanding treatment options to the 4% of DMD patients with exon 52 mutations

Inventive Principle:

Principle #35Parameter changes

3Manufacturing precision

If PMO molecules are designed to hybridize to DMD pre-mRNA to induce exon 52 skipping, then truncated but functional dystrophin protein is produced, but the specific hybridization target must be precisely identified

Engineering Contradiction:

Improveexon skipping specificityVSAvoidPMO sequence design

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The PMO sequence is designed in advance to hybridize to a specific region of exon 52 in the DMD pre-mRNA transcript. The sequence is pre-optimized to ensure high-affinity binding and effective induction of exon skipping, allowing the conjugate to be manufactured with defined specificity before administration to patients

Inventive Principle:

Principle #10Preliminary action

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 PMO-antibody conjugates effectively induce exon 52 skipping in muscle cells, leading to the production of a functional, truncated dystrophin protein, potentially providing a therapeutic breakthrough for DMD patients.

Implementation Method 1

a PMO molecule that hybridizes to a pre-mRNA transcript of the DMD gene and induces exon 52 skipping

Methodology Applied

Scientific EffectNucleic acid hybridization:

Implementation Method 2

phosphorodiamidate morpholino oligonucleotide (PMO) conjugates comprising an anti-transferrin receptor antibody or antigen binding fragment thereof conjugated to a PMO molecule

Methodology Applied

Scientific EffectAntibody-antigen binding:

Data Source

PatentUS20250325694A1Antibody-oligonucleotide conjugate compositions and methods of inducing DMD exon 52 skipping

Publication Date: 2025.10.23 AVIDITY BIOSCI INC

AI summary

Disclosed herein are antibody-oligonucleotide conjugates and pharmaceutical compositions comprising the antibody-oligonucleotide conjugates that induce an alteration in an incorrectly spliced dystrophin mRNA transcript to induce DMD exon 52 skipping. Also described herein include methods for treating muscle dystrophy including Duchenne muscular dystrophy by administering antibody-oligonucleotide conjugates or a pharmaceutical composition comprising the antibody-oligonucleotide conjugates that induce an alteration in an incorrectly spliced dystrophin mRNA transcript to induce DMD exon 52 skipping.