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
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
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
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
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
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
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
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
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)
Article
Medicine, Research & Experimental
Liubov Gushchina, Adrienne J. Bradley, Tatyana A. Vetter, Jacob W. Lay, Natalie L. Rohan, Emma C. Frair, Nicolas Wein, Kevin M. Flanigan
Summary: Duchenne muscular dystrophy (DMD) is a progressive disease caused by mutations in the DMD gene, and an exon-skipping strategy has shown long-term protection and dystrophin expression in Dup2 mutation models.
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
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
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)
Article
Medicine, Research & Experimental
Cedric Happi Mbakam, Joel Rousseau, Yaoyao Lu, Anne Bigot, Kamel Mamchaoui, Vincent Mouly, Jacques P. Tremblay
Summary: In this study, researchers used CRISPR-Cas9 prime editing technology to correct a mutation in the DMD gene, resulting in improved editing efficiency and restoration of dystrophin protein expression. Optimization of the reverse transcription template sequence led to a significant increase in the editing percentage of the target nucleotide.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Cell & Tissue Engineering
Basma Benabdallah, Cynthia Desaulniers-Langevin, Marie-Lyn Goyer, Chloe Colas, Chantale Maltais, Yuanyi Li, Jean V. Guimond, Jacques P. Tremblay, Elie Haddad, Christian Beausejour
Summary: In the study, it was found that autologous cell engraftment was tolerated while allogeneic grafts were rejected in humanized mouse models. Additionally, hiPSC-derived myogenic progenitor cells (MPCs) were not targeted by autologous T cells and natural killer cells in vitro. These findings suggest that hiPSC-derived MPCs may be tolerated in the presence of a competent human immune system.
STEM CELLS TRANSLATIONAL MEDICINE
(2021)
Editorial Material
Biotechnology & Applied Microbiology
Jacques P. Tremblay, Andrea Annoni, Masataka Suzuki
Article
Biochemistry & Molecular Biology
Pouire Yameogo, Benjamin L. Duchene, Nathalie Majeau, Jacques P. Tremblay
Summary: CRISPR/Cas9 has opened up opportunities for genetic mutation correction therapies, yet long-term expression of the Cas9 gene can lead to off-target mutations and immune responses. A drug-inducible system was proposed to limit the expression of Cas9 nuclease. Through introducing a premature termination codon (PTC) and treatment with an aminoglycoside drug, it was demonstrated that Cas9 protein expression can be controlled effectively.
Article
Clinical Neurology
Cedric Happi Mbakam, Gabriel Lamothe, Guillaume Tremblay, Jacques P. Tremblay
Summary: The discovery of CRISPR-Cas system has brought new possibilities in precision medicine, particularly in the correction of Duchenne muscular dystrophy mutations. However, there are challenges to be addressed before its clinical application, such as off-target editing, efficient delivery, immune response, and vector issues.
Article
Genetics & Heredity
Guillaume Tremblay, Joel Rousseau, Cedric Happi Mbakam, Jacques P. Tremblay
Summary: Alzheimer's disease is caused by abnormal processing of APP, which leads to the formation of toxic beta-amyloid peptides. The A673T mutation prevents this processing and protects against AD development. This study demonstrates the use of CRISPR prime editing to precisely introduce the A673T mutation, offering potential for further research and treatment of AD.
Article
Biotechnology & Applied Microbiology
Nathalie Majeau, Annabelle Fortin-Archambault, Catherine Gerard, Joel Rousseau, Pouire Yameogo, Jacques P. Tremblay
Summary: In this study, a simple method was developed to load CRISPR ribonucleoproteins (RNPs) into extracellular vesicles (EVs), which successfully restored the expression of fluorescent proteins in muscle fibers and achieved deletion of the DMD gene in mdx mice. This provides new opportunities for treating DMD.
Review
Medicine, General & Internal
Cedric Happi Mbakam, Gabriel Lamothe, Jacques P. Tremblay
Summary: This article provides an update on therapeutic strategies for Duchenne muscular dystrophy (DMD), including approaches to restore dystrophin expression and ongoing experimental methods.
FRONTIERS IN MEDICINE
(2022)
Review
Pharmacology & Pharmacy
Kelly Godbout, Jacques P. Tremblay
Summary: Gene therapy has the potential to treat genetic diseases, but the delivery of CRISPR-derived technologies to specific organs remains a challenge. Lipid nanoparticles (LNPs) have emerged as a promising delivery method, but most of the cargo is trapped by the liver when delivered intravenously, and directly injecting them into organs requires more invasive procedures. Therefore, developing more specific LNPs is crucial for their future clinical use.
Article
Multidisciplinary Sciences
Pouire Yameogo, Nathalie Majeau, Cedric Happi Mbakam, Jacques P. Tremblay
Summary: The small size of CjCas9 allows for easier vectorization in in vivo gene therapy. However, it is generally less efficient than SpCas9 in generating indels in target genes, and the factors affecting its efficiency have not been determined. In our study, we found that the protein levels of CjCas9 expressed in HEK293T cells were significantly lower than those of SpCas9. We investigated the effect of proteasome inhibitors on CjCas9 protein stability and its efficiency in editing the FXN gene.
Article
Medicine, Research & Experimental
Cedric Happi Mbakam, Joel Rousseau, Yaoyao Lu, Anne Bigot, Kamel Mamchaoui, Vincent Mouly, Jacques P. Tremblay
Summary: In this study, researchers used CRISPR-Cas9 prime editing technology to correct a mutation in the DMD gene, resulting in improved editing efficiency and restoration of dystrophin protein expression. Optimization of the reverse transcription template sequence led to a significant increase in the editing percentage of the target nucleotide.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Biochemistry & Molecular Biology
Pouire Yameogo, Catherine Gerard, Nathalie Majeau, Jacques P. Tremblay
Summary: Most cases of Friedreich ataxia (FRDA) are caused by the elongation of the GAA repeat sequence in the FXN gene, resulting in a decrease in frataxin protein expression. Deletion of the GAA repeat using CRISPR/Cas9 technology has been shown to increase frataxin expression in vitro. This study aims to develop a FRDA treatment by deleting the GAA repeat using CRISPR/Cas9 technology with a single AAV vector expressing CjCas9 and two sgRNAs targeting the FXN gene. Although some GAA repeat deletions were observed in the heart and liver of mouse models, the editing rate was not sufficient to increase frataxin mRNA in the heart. However, the correlation between the editing rate and AAV distribution suggests the potential of using a better delivery tool for the CRISPR/Cas9 system in FRDA therapy.
Review
Cell Biology
Kelly Godbout, Jacques P. Tremblay
Summary: Gene therapy has great potential in treating inherited diseases by addressing the root genetic mutations. The discovery of CRISPR/Cas9 in 2012 paved the way for the development of gene therapies, including the recent technology called prime editing, which enables targeted alterations in the human genome. Prime editing has been attempted in various preclinical studies and shows promise as a treatment for genetic diseases.
Article
Genetics & Heredity
Camille Bouchard, Catherine Gerard, Solange Gni-fiene Yanyabe, Nathalie Majeau, Malek Aloui, Gabrielle Buisson, Pouire Yameogo, Vanessa Couture, Jacques P. Tremblay
Summary: This study aimed to find an optimized mouse model with a phenotype comparable to human patients for studying the impact of therapy. By comparing two mouse models (YG8sR and YG8-800) with healthy mice (Y47R) in behavior tests, significant differences were noticed between YG8sR mice injected with anti-FXN shRNA and YG8-800 mice compared to healthy mice. In conclusion, YG8sR mice have a slight phenotype, and injecting them with an AAV-PHP.B expressing anti-FXN shRNA does increase their phenotype; YG8-800 mice have a phenotype comparable to the human ataxic phenotype.
Review
Medicine, General & Internal
Camille Bouchard, Jacques P. Tremblay
Summary: Dysferlinopathy is a disease caused by mutations in the DYSF gene, leading to a deficiency of dysferlin. It typically manifests during teenage years or young adulthood with symptoms such as loss of Achilles tendon reflexes and difficulty in standing on tiptoes or climbing stairs, followed by progressive muscle weakness. Recent advancements in tools and mouse models have improved diagnosis and research for this condition.
JOURNAL OF CLINICAL MEDICINE
(2023)
Review
Medicine, General & Internal
Camille Bouchard, Jacques P. Tremblay
Summary: This review article presents 39 genes associated with limb-girdle muscular dystrophies (LGMDs), which can be inherited dominantly or recessively. The classification of LGMDs has evolved over time and now requires a mutation causing proximal muscle weakness found in multiple unrelated families. The article also discusses available and developing therapies for LGMDs, aiming to address the root cause of the disease instead of treating individual symptoms.
JOURNAL OF CLINICAL MEDICINE
(2023)
