Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies

  title={Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies},
  author={Jaeho Hwang and Toshifumi Yokota},
  journal={Expert Reviews in Molecular Medicine},
Abstract Muscular dystrophy is a group of genetic disorders characterised by degeneration of muscles. Different forms of muscular dystrophy can show varying phenotypes with a wide range of age, severity and location of muscle deterioration. Many palliative care options are available for muscular dystrophy patients, but no curative treatment is available. Exon-skipping therapy aims to induce skipping of exons with disease-causing mutations and/or nearby exons to restore the reading frame, which… 

Antisense and Gene Therapy Options for Duchenne Muscular Dystrophy Arising from Mutations in the N-Terminal Hotspot

This review summarizes the current state of development of N-terminal antisense and gene therapies for DMD, mainly focusing on exon-skipping therapy for duplications and deletions, as well as microdystrophin therapy.

Restoring Protein Expression in Neuromuscular Conditions: A Review Assessing the Current State of Exon Skipping/Inclusion and Gene Therapies for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy.

  • O. SheikhT. Yokota
  • Biology, Medicine
    BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy
  • 2021
Antisense oligonucleotide-mediated exon skipping and inclusion therapies are advancing clinically and gene therapy for DMD has strong potential to restore dystrophin expression in patients, and antisense and gene therapies stand poised to elevate the lives of patients with DMD and SMA.

Structural Perturbations of Exon Skipping Edits within the Dystrophin D20:24 Region

A systematic and comprehensive panel of possible exon cuts in a region of the dystrophin protein is examined, and for the first time, exon edits that appear to maintain structural stability similar to wildtype protein are identified.

CRISPR Therapeutics for Duchenne Muscular Dystrophy

Gene editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system is a promising therapeutic for DMD, as it can permanently correct DMD mutations and thus restore the reading frame, allowing for the production of functional dystrophin.

Personalized Development of Antisense Oligonucleotides for Exon Skipping Restores Type XVII Collagen Expression in Junctional Epidermolysis Bullosa

It is assumed AON-mediated exon skipping to be a promising tool for the treatment of junctional epidermolysis bullosa, particularly applicable in a personalized manner for rare genotypes.

The lncRNA 44s2 Study Applicability to the Design of 45-55 Exon Skipping Therapeutic Strategy for DMD

Results suggest that lncRNA44s2 could be involved in muscle differentiation process and become a potential disease progression biomarker for Duchenne and Becker muscular dystrophy, and propose that the design of the CRISPR/Cas9 MES45-55 assay consider the lnc RNA sequences bordering the exonic 45 to 55 deletion.

[CRISPR-Cas9 for muscle dystrophies].

The latest therapeutic advances obtained using the CRISPR-Cas9 system in genetic muscular dystrophies are discussed, which should make it possible to avoid long, partially efficient and repetitive treatments.

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

The current FDA-approved antisense MoA and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation are reviewed.

From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases.

RNA-targeted therapies (e.g. apo(a)-ASO and PCSK9-siRNA) are now in large-scale clinical outcome trials and will most likely become a novel effective and safe therapeutic option for CVD in the near future.



Skipping Multiple Exons to Treat DMD—Promises and Challenges

Significant changes are needed in the drug approval process to promote the cocktail AO approach, because both exons 6 and 8 need to be skipped to restore the reading frame in dystrophic dogs and the current drug approval system is not designed to evaluate such circumstances.

Therapeutic exon skipping for dysferlinopathies?

The dysferlin protein domains and DYSF mutations are analyzed and what exons are promising targets with regard to applicability and feasibility are described and it is shown that DysF exon skipping seems to be as straightforward as DMD exon skipped, as AONs to induce efficient skipping of four DYSf exons were readily identified.

Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping.

The potential for exon skipping has been expanded by testing whether an internal, in-frame truncation of a transmembrane protein γ-sarcoglycan is functional, and an internally truncated Γ-sARCoglycan protein is generated, termed Mini-Gamma by deleting a large portion of the extracellular domain.

Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients.

The broad therapeutic applicability of the antisense-induced skipping of targeted exons from the pre-mRNA is demonstrated in cultured muscle cells from six DMD patients carrying different deletions and a nonsense mutation, restoring dystrophin synthesis in over 75% of cells.

Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: Current Status of Therapeutic Approaches

The current status of therapeutic approaches for DMD is reviewed, focusing on therapeutic approaches that can restore dystrophin.

Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse.

This approach should reduce the severity of DMD by allowing a dystrophic gene transcript to be modified, such that it can be translated into a Becker-dystrophin-like protein.

Bodywide skipping of exons 45–55 in dystrophic mdx52 mice by systemic antisense delivery

A unique successful demonstration of effective rescue by exon 45–55 skipping in a dystrophin-deficient animal model is demonstrated.

Exon skipping for nonsense mutations in Duchenne muscular dystrophy: too many mutations, too few patients?

The world-wide database containing notations for more than 1200 patients with nonsense mutations is examined, discussing progress and remaining hurdles in exon skipping and an alternative strategy, stop-codon readthrough.