Article
Multidisciplinary Sciences
Pablo Beckers, Jean-Hubert Caberg, Vinciane Dideberg, Tamara Dangouloff, Johan T. den Dunnen, Vincent Bours, Laurent Servais, Francois Boemer
Summary: This study developed a highly sensitive method to identify DMD patients carrying deletions that are rescuable by exon-skipping treatment. By analyzing the exons flanking the exon-skipping targets, patients who could benefit from exon-skipping treatment can be identified early on.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Elena Gargaun, Sestina Falcone, Guilhem Sole, Julien Durigneux, Andoni Urtizberea, Jean Marie Cuisset, Sofia Benkhelifa-Ziyyat, Laura Julien, Anne Boland, Florian Sandron, Vincent Meyer, Jean Francois Deleuze, David Salgado, Jean-Pierre Desvignes, Christophe Beroud, Anatole Chessel, Alexia Blesius, Martin Krahn, Nicolas Levy, France Leturcq, France Pietri-Rouxel
Summary: This study found that long noncoding RNAs play important roles in Duchenne and Becker muscular dystrophy, particularly in regulating myocyte proliferation and differentiation with potential therapeutic implications. The research suggests that lncRNA44s2 may serve as an accelerator in muscle differentiation process and is associated with a favorable clinical phenotype.
Article
Medicine, Research & Experimental
Flavien Bizot, Remko Goossens, Thomas Tensorer, Sergei Dmitriev, Luis Garcia, Annemieke Aartsma-Rus, Pietro Spitali, Aurelie Goyenvalle
Summary: This study found that histone deacetylase inhibitors can correct the imbalance of transcripts in patients with Duchenne muscular dystrophy, and the combined therapy with antisense oligonucleotides can significantly improve the restoration levels of dystrophin.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Pharmacology & Pharmacy
Grant Patterson, Haley Conner, Mecham Groneman, Cyril Blavo, Mayur S. Parmar
Summary: Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that causes muscle weakness and atrophy. It is diagnosed in early childhood and progresses over time, often leading to death in early adulthood. The current treatment options for DMD focus on improving quality of life and slowing down the progression of symptoms. New approaches, such as gene transfer therapy and exon skipping agents, show promise in providing more effective treatment. This review discusses the pathogenesis of DMD and explores both current and emerging therapeutic options.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Medicine, Research & Experimental
Tabatha R. Simmons, Tatyana A. Vetter, Nianyuan Huang, Adeline Vulin-Chaffiol, Nicolas Wein, Kevin M. Flanigan
Summary: This study developed an adeno-associated virus-based exon-skipping approach targeted at duplications of exon 2 in the DMD gene, which represent 10% of all DMD duplication mutations. Deletion of exon 2 results in the utilization of an internal ribosome entry site in exon 5, allowing translation of a highly protective dystrophin protein, providing a wide therapeutic window for treatment. Both intramuscular and systemic administration of this vector in the Dup2 mouse model resulted in robust dystrophin expression and correction of muscle physiologic defects, allowing dose escalation to establish a putative minimal efficacious dose for a human clinical trial.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2021)
Article
Biochemistry & Molecular Biology
Cody A. Desjardins, Monica Yao, John Hall, Emma O'Donnell, Reshmii Venkatesan, Sean Spring, Aiyun Wen, Nelson Hsia, Peiyi Shen, Ryan Russo, Bo Lan, Tyler Picariello, Kim Tang, Timothy Weeden, Stefano Zanotti, Romesh Subramanian, Oxana Ibraghimov-Beskrovnaya
Summary: The study developed a platform called FORCE that enhances the delivery of phosphorodiamidate morpholino oligomers (PMO) in muscles, enabling exon skipping and dystrophin restoration in patients with muscular dystrophy. FORCE treatment improved functional outcomes compared to unconjugated drugs.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Health Care Sciences & Services
Saeed Anwar, Merry He, Kenji Rowel Q. Lim, Rika Maruyama, Toshifumi Yokota
Summary: This study found that five exons are associated with significantly milder phenotypes, while most exon skip-equivalent in-frame deletions were associated with a significantly milder phenotype compared to corresponding exon skip-amenable out-of-frame mutations. This highlights the importance of genotype-phenotype correlation studies in the rational design of exon-skipping therapies.
JOURNAL OF PERSONALIZED MEDICINE
(2021)
Article
Medicine, Research & Experimental
Hiroaki Ohara, Motoyasu Hosokawa, Tomonari Awaya, Atsuko Hagiwara, Ryo Kurosawa, Yukiya Sako, Megumu Ogawa, Masashi Ogasawara, Satoru Noguchi, Yuichi Goto, Ryosuke Takahashi, Ichizo Nishino, Masatoshi Hagiwara
Summary: The FKTN c.647+2084G>T variant causes Fukuyama congenital muscular dystrophy (FCMD) by creating a pseudo-exon. Researchers discovered that the branchpoint, essential for splicing reactions, can be a potential therapeutic target. Through the design of branchpoint-targeted antisense oligonucleotides (BP-AONs), they successfully restored normal FKTN mRNA and protein production in FCMD patient myotubes. This suggests that branchpoints could be potential targets in exon-skipping therapeutic strategies for genetic disorders.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2023)
Review
Toxicology
Omar Sheikh, Toshifumi Yokota
Summary: Duchenne muscular dystrophy (DMD) is a severe genetic disease with no current cure. Eteplirsen, a promising exon-skipping therapy, faces challenges with low production of dystrophin and limited efficacy in the heart.
ARCHIVES OF TOXICOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Judith van Deutekom, Chantal Beekman, Suzanne Bijl, Sieto Bosgra, Rani van den Eijnde, Dennis Franken, Bas Groenendaal, Bouchra Harquouli, Anneke Janson, Paul Koevoets, Melissa Mulder, Daan Muilwijk, Galyna Peterburgska, Bianca Querido, Janwillem Testerink, Ruurd Verheul, Peter de Visser, Rudie Weij, Annemieke Aartsma-Rus, Jukka Puolivali, Timo Bragge, Charles O'Neill, Nicole A. Datson
Summary: In the last two decades, antisense oligonucleotides (AONs) have shown promising potential as therapies for Duchenne muscular dystrophy (DMD) patients. However, the efficacy of current AONs is limited, and there is a need for improvement in developing more efficient treatments.
NUCLEIC ACID THERAPEUTICS
(2023)
Article
Medicine, Research & Experimental
Matthew Rok, Tatianna Wai Ying Wong, Eleonora Maino, Abdalla Ahmed, Grace Yang, Elzbieta Hyatt, Kyle Lindsay, Sina Fatehi, Ryan Marks, Paul Delgado-Olguin, Evgueni A. Ivakine, Ronald D. Cohn
Summary: This study demonstrates that intravenous delivery of a single-cut CRISPR-Cas9-mediated exon skipping therapy can prevent heart dysfunction in DMD in vivo.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2023)
Article
Multidisciplinary Sciences
Kenji Rowel Q. Lim, Stanley Woo, Dyanna Melo, Yiqing Huang, Kasia Dzierlega, Md Nur Ahad Shah, Tejal Aslesh, Rohini Roy Roshmi, Yusuke Echigoya, Rika Maruyama, Hong M. Moulton, Toshifumi Yokota
Summary: This study focuses on the development of peptide-conjugated PMOs for exons 45 to 55 skipping in Duchenne muscular dystrophy (DMD). The results demonstrate that targeting as few as five exons can achieve exon skipping, and conjugating a cell-penetrating peptide to PMOs improves the skipping efficiency. This study provides a proof of concept for the development of a more economical and effective treatment for DMD.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Genetics & Heredity
Mario Abaji, Svetlana Gorokhova, Nathalie Da Silva, Tiffany Busa, Maude Grelet, Chantal Missirian, Sabine Sigaudy, Nicole Philip, France Leturcq, Nicolas Levy, Martin Krahn, Marc Bartoli
Summary: Exon skipping is a promising therapeutic approach, where it is crucial to ensure the exon-skipped form of the gene can partially perform the required function and improve phenotype. Discovery of a deletion of in-frame exon 49 in the DMD gene opens up possibilities to extend exon skipping approaches for patients carrying truncating mutations in exon 49.
Article
Multidisciplinary Sciences
Michael Stirm, Bachuki Shashikadze, Andreas Blutke, Elisabeth Kemter, Andreas Lange, Jan B. Stoeckl, Florian Jaudas, Laeticia Laane, Mayuko Kurome, Barbara Kessler, Valeri Zakhartchenko, Andrea Baehr, Nikolai Klymiuk, Hiroshi Nagashima, Maggie C. Walter, Wolfgang Wurst, Christian Kupatt, Thomas Froehlich, Eckhard Wolf
Summary: Skipping DMD exon 51 can restore dystrophin expression and improve cardiac function in DMD patients and animal models.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemical Research Methods
Wilson Louie, Max W. Shen, Zakir Tahiry, Sophia Zhang, Daniel Worstell, Christopher A. Cassa, Richard I. Sherwood, David K. Gifford
Summary: Using machine learning to select effective Cas9 guide RNAs that induce exon skipping shows promise for evaluating CRISPR-Cas9-mediated exon skipping therapy.
PLOS COMPUTATIONAL BIOLOGY
(2021)
