MedPath

Novel Cytosine Base Editor Restores Dystrophin Expression in DMD Mouse Model

• Researchers have developed a novel cytosine base editor (aTdCBE) that lacks adenosine deaminase activity, enhancing its precision in gene editing. • In a humanized mouse model of Duchenne muscular dystrophy (DMD), aTdCBE effectively corrected exon 55 splicing by targeting the splice acceptor site. • Treatment with aTdCBE led to nearly 99% restoration of dystrophin-positive muscle fibers and approximately 60% restoration of dystrophin expression. • The study demonstrates the potential of aTdCBE to restore the correct reading frame of the DMD gene, leading to functional dystrophin protein production.

A novel cytosine base editor (CBE) has shown promise in restoring dystrophin expression in a humanized mouse model of Duchenne muscular dystrophy (DMD). The study, conducted by researchers from HuidaGene Therapeutics and other institutions in China and published in Nature Communications, addresses the challenge of existing tRNA-specific adenosine deaminase (TadA) variants exhibiting dual activity on both cytosine and adenosine bases. The newly developed aTdCBE lacks adenosine deaminase activity, enhancing its precision for targeted gene editing.
The research focused on correcting exon 55 splicing in a DMD mouse model with a deletion in exon 54 of the DMD gene. This deletion results in a premature stop codon in exon 55, leading to the production of a non-functional dystrophin protein. The objective was to restore dystrophin expression by skipping exon 55 through precise cytosine base editing at the exon 55 splice acceptor site (SAS).

Efficacy of aTdCBE in DMD Mouse Model

Following in vivo delivery of aTdCBE, DNA base editing at the exon 55 splice acceptor site reached over 40% after six weeks, indicating effective editing of the DMD gene. Immunostaining revealed that dystrophin-positive muscle fibers reached almost 99% of wild-type levels. Western blot analysis confirmed approximately 60% restoration of dystrophin expression.

Molecular Confirmation of Dystrophin Restoration

RT-PCR analysis further validated successful exon 55 skipping, restoring the correct reading frame of the DMD gene. This led to the production of functional dystrophin protein, demonstrating efficient gene editing and significant dystrophin restoration in the treated mice. These results suggest a potential therapeutic strategy for DMD by precisely correcting genetic mutations at the DNA level.

Implications for DMD Treatment

Duchenne muscular dystrophy is a severe genetic disorder characterized by progressive muscle degeneration and weakness. Current treatments offer limited efficacy, highlighting the urgent need for innovative therapeutic approaches. This study introduces a promising gene editing strategy that could potentially address the underlying genetic cause of DMD, offering a more effective and targeted treatment option.
Subscribe Icon

Stay Updated with Our Daily Newsletter

Get the latest pharmaceutical insights, research highlights, and industry updates delivered to your inbox every day.

Related Topics

CRISPR Repairs Limb-Girdle Muscular Dystrophy 2B Mutation and Phenotypes in Patient-Derived Cells

Researchers have developed a CRISPR-based gene correction strategy to restore dysferlin function in cells from patients with limb-girdle muscular dystrophy 2B (LGMD2B), a rare genetic disorder. This approach successfully corrected a common frameshift mutation in the DYSF gene, leading to the restoration of full-length, functional dysferlin protein in patient-derived cells and a newly developed mouse model.

Experimental Drug K884 Enhances Muscle Stem Cell Repair in Duchenne Muscular Dystrophy

Researchers at McGill University discovered that K884 enhances muscle stem cell repair in Duchenne muscular dystrophy (DMD).
K884 targets DMD-affected cells regardless of the mutation, promoting functional muscle development, unlike gene therapies.

Elevidys Gene Therapy Shows Sustained Benefits in Duchenne Muscular Dystrophy Patients

Sarepta Therapeutics' Elevidys demonstrates sustained benefits and disease stabilization in ambulatory Duchenne muscular dystrophy (DMD) patients, according to Phase 3 EMBARK trial results.
Crossover-treated patients showed a 2.34-point improvement on the North Star Ambulatory Assessment (NSAA) compared to matched external controls after 52 weeks of Elevidys treatment.

StitchR Gene Therapy Enables Treatment for Muscular Dystrophies and Large-Gene Diseases

A novel gene therapy technology called StitchR overcomes size limitations in gene delivery for treating muscular dystrophies and other diseases involving large genes.
StitchR uses a dual vector system to deliver two halves of a gene separately, which then combine to restore the expression of missing or inactive proteins.

CRISPR-Cas9 Corrects Dystrophin Duplications in DMD Patient Cells

Researchers used CRISPR-Cas9 to target intronic regions in the _DMD_ gene in patient cells, aiming to delete duplicated regions.
The study confirmed restoration of the _DMD_ open reading frame and rescued dystrophin expression after CRISPR-based deletion.

FDA Grants Orphan Drug and Rare Pediatric Disease Designations for Duchenne Muscular Dystrophy Therapies

Ractigen's RAG-18, an RNA activation agent targeting utrophin, received orphan drug designation for Duchenne and Becker muscular dystrophy, offering development incentives.
Neu-REFIX Beta glucan, an oral food supplement, also obtained rare pediatric disease and orphan drug designations for DMD treatment, facilitating clinical trials in the US.

FDA Expands Approval of Elevidys Gene Therapy for Duchenne Muscular Dystrophy to Wider Patient Population

The FDA has broadened the approval of delandistrogene moxeparvovec-rokl (Elevidys) for Duchenne muscular dystrophy (DMD) to include both ambulatory and non-ambulatory patients aged 4 and older.
This decision grants traditional approval for ambulatory individuals and accelerated approval for non-ambulatory individuals, addressing a critical unmet need in DMD treatment.

FDA Approves Elevidys, a Gene Therapy for Duchenne Muscular Dystrophy

The FDA has granted accelerated approval to Elevidys, the first gene therapy for Duchenne muscular dystrophy (DMD) in certain pediatric patients aged 4-5.
Elevidys works by delivering a gene that leads to the production of a shortened, functional micro-dystrophin protein in muscle cells.

Advancements in AAV Gene Therapy for Duchenne Muscular Dystrophy Show Promise

AAV-mediated gene therapy is emerging as a promising strategy for treating Duchenne Muscular Dystrophy (DMD) by restoring dystrophin expression.
Micro-dystrophin gene transfer using AAV vectors has demonstrated therapeutic success in large animal models, paving the way for human clinical trials.

CRISPR Gene Editing Restores Dystrophin Expression in Canine DMD Model

Systemic delivery of CRISPR gene editing components restored dystrophin expression in skeletal muscle of DMD dogs, ranging from 3 to 90% of normal levels.
Cardiac muscle dystrophin levels reached 92% of normal in the dog receiving the highest dose, demonstrating significant cardiac muscle restoration.

Reference News

[1]
Enhanced Cytosine Base Editing for Duchenne Muscular Dystrophy - CRISPR Medicine
crisprmedicinenews.com · Sep 17, 2024

Chinese researchers developed aTdCBE, a novel cytosine base editor lacking adenosine deaminase activity, to correct exon...

© Copyright 2025. All Rights Reserved by MedPath
HomeTerms & ConditionsPrivacy Policy