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
Veterinary Sciences
Sarah M. Schneider, Garett T. Sansom, Lee-Jae Guo, Shinji Furuya, Brad R. Weeks, Joe N. Kornegay
Summary: This study systematically assessed cardiac lesions in carrier dogs, GRMD dogs, and normal dogs, and found that quantitative analysis of the cross-sectional area of fibrosis can distinguish the health status of different groups of dogs. The features identified in GRMD dogs are compatible with those of DMD, validating GRMD as an effective model for studying cardiomyopathy.
FRONTIERS IN VETERINARY SCIENCE
(2022)
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
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
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
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
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
Katarzyna Chwalenia, Jacopo Oieni, Joanna Zemla, Malgorzata Lekka, Nina Ahlskog, Anna M. L. Coenen-Stass, Graham McClorey, Matthew J. A. Wood, Yulia Lomonosova, Thomas C. Roberts
Summary: This study aimed to determine whether exon skipping using a peptide-phosphorodiamidate morpholino oligonucleotide (PPMO) conjugate results in dose-dependent restoration of uniform dystrophin localization in DMD patients. The results demonstrated that PPMO-mediated exon skipping generates myofibers with uniform dystrophin expression and restores serum microRNA biomarkers and muscle stiffness in a dose-dependent manner. These findings suggest the potential utility of PPMO as a therapeutic approach for restoring dystrophin in DMD.
MOLECULAR THERAPY-NUCLEIC ACIDS
(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
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
Medicine, General & Internal
Cedric Happi Mbakam, Jeanne Roustant, Joel Rousseau, Pouire Yameogo, Yaoyao Lu, Anne Bigot, Kamel Mamchaoui, Vincent Mouly, Gabriel Lamothe, Jacques P. Tremblay
Summary: In this study, the CRISPR-Cas9 Prime editing technology was used to develop strategies to correct frameshift mutations in the DMD gene carrying exon 52 deletion or exons 45 to 52 deletion. Through the use of optimized epegRNAs, specific substitutions, deletions, and insertions were induced in the splice donor sites for exons 51 and 53. These modifications resulted in the skipping of exons 51 and 53 and restored the expression of dystrophin. Overall, Prime editing successfully corrected frameshift mutations in the DMD gene.
FRONTIERS IN MEDICINE
(2023)
Article
Multidisciplinary Sciences
Paul T. Martin, Deborah A. Zygmunt, Anna Ashbrook, Sonia Hamilton, Davin Packer, Sharla M. Birch, Amanda K. Bettis, Cynthia J. Balog-Alvarez, Lee-Jae Guo, Peter P. Nghiem, Joe N. Kornegay
Summary: Short-term intravenous treatment of GRMD dogs with rAAVrh74.MHCK7.GALGT2 at high doses can induce muscle glycosylation and utrophin expression over a short 3-month interval, showing modest effects on muscle pathology and no significant improvement on muscle strength. Serum chemistry, hematology, and cardiac function measures were largely unchanged by treatment.
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
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
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
Biochemistry & Molecular Biology
Karima Relizani, Lucia Echevarria, Faouzi Zarrouki, Cecile Gastaldi, Chloe Dambrune, Philippine Aupy, Adrian Haeberli, Marek Komisarski, Thomas Tensorer, Thibaut Larcher, Fedor Svinartchouk, Cyrille Vaillend, Luis Garcia, Aurelie Goyenvalle
Summary: Tricyclo-DNA (tcDNA) is a promising oligonucleotide analog with therapeutic potential, especially when conjugated with palmitic acid for improved delivery to muscle tissues. This conjugation enhances the potency of tcDNA-ASO, resulting in functional improvement in dystrophic mice with significantly reduced dose, while also showing a promising safety profile for clinical development in neuromuscular diseases.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Clinical Neurology
Faouzi Zarrouki, Karima Relizani, Flavien Bizot, Thomas Tensorer, Luis Garcia, Cyrille Vaillend, Aurelie Goyenvalle
Summary: This study aimed to evaluate whether restoring brain dystrophin could alleviate cognitive and behavioral deficits associated with Duchenne muscular dystrophy. The results showed that exon skipping treatment in mdx mice significantly reduced fear responses and improved long-term memory retention.
ANNALS OF NEUROLOGY
(2022)
Article
Cell Biology
Johann Bohm, Ines Barthelemy, Charlene Landwerlin, Nicolas Blanchard-Gutton, Frederic Relaix, Stephane Blot, Jocelyn Laporte, Laurent Tiret
Summary: Mutations in the DNM2 gene cause autosomal dominant centronuclear myopathy. A dog model with the same mutation as the most common mutation found in humans was created, and the dog offspring showed muscle atrophy and mildly impaired gait, similar to the human disorder.
DISEASE MODELS & MECHANISMS
(2022)
Review
Cardiac & Cardiovascular Systems
Omar Soukarieh, Caroline Meguerditchian, Carole Proust, Dylan Aissi, Melanie Eyries, Aurelie Goyenvalle, David-Alexandre Tregouet
Summary: HTS technologies are transforming research and molecular diagnostics by exploring millions of nucleotide sequences, focusing on identifying genetic variations contributing to rare and common human diseases. The study highlights the importance of 5'UTR variants altering upORFs and their association with rare cardiovascular disorders.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2022)
Article
Veterinary Sciences
Thibaut Troupel, Nicolas Van Caenegem, Carole Drougard, Nicolas Blanchard-Gutton, Stephane Blot
Summary: This article reports a rare case of myositis in a dog, showing clinical signs consistent with masticatory myositis but with negative autoantibodies against myofibers, suggesting the possibility of generalized idiopathic polymyositis. This case highlights the importance of multiple muscle biopsies and extended immunohistochemical studies in canine myositis.
VETERINARY RECORD CASE REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Faouzi Zarrouki, Sebastien Goutal, Ophelie Vacca, Luis Garcia, Nicolas Tournier, Aurelie Goyenvalle, Cyrille Vaillend
Summary: This study found that the loss of dystrophin in a mouse model of Duchenne muscular dystrophy (DMD) affects not only the stability of synaptic GABA(A) receptors, but also the composition and expression of subunits at both synaptic and extrasynaptic sites. These findings provide new measures to evaluate compensation for nervous system alterations in DMD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Veterinary Sciences
Nicolas Van Caenegem, Thibaut Troupel, Jeremy Mortier, Jean-Laurent Thibaud, Stephane Blot
Summary: This article presents a case of a 3-year-old female German Shepherd dog with generalized tonic-clonic epileptic seizures, central vestibular syndrome, and trigeminal nerve dysfunction. Magnetic resonance imaging revealed multiple acute ischemic and hemorrhagic strokes, leading to ischemia and infarctions in various organs. The dog showed improvement after medical management, surgery, and intensive rehabilitation.
JOURNAL OF VETERINARY INTERNAL MEDICINE
(2022)
Article
Multidisciplinary Sciences
Adrien Morin, Amalia Stantzou, Olga N. Petrova, John Hildyard, Thomas Tensorer, Meriem Matouk, Mina V. Petkova, Isabelle Richard, Tudor Manoliu, Aurelie Goyenvalle, Sestina Falcone, Markus Schuelke, Corinne Laplace-Builhe, Richard J. Piercy, Luis Garcia, Helge Amthor
Summary: Dystrophin is crucial for muscle health, but its spatial organization is not well understood. Studying fluorescently tagged dystrophin in mice, researchers discovered that dystrophin is compartmentalized in sarcolemmal territories. At myotendinous junctions, Dmd transcripts and dystrophin protein are enriched. Genomic correction restored separated dystrophin domains, while transcript-level correction restored dystrophin initially at junctions before extending along the entire fiber. This research suggests that widespread restoration of fiber dystrophin, especially at muscle-tendon junctions, is critical for therapeutic success in DMD.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Aurelie Goyenvalle, Cecilia Jimenez-Mallebrera, Willeke van Roon, Sabine Sewing, Arthur M. Krieg, Virginia Arechavala-Gomeza, Patrik Andersson
Summary: The field of nucleic acid therapeutics has seen significant progress, but early assessments of toxicity have often been neglected. Consensus recommendations have been proposed to evaluate the toxicity of nucleic acid drugs in early stages, including the use of predictive in vitro and ex vivo assays to filter out potentially toxic candidates before animal studies.
NUCLEIC ACID THERAPEUTICS
(2023)
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
Veterinary Sciences
Nicolas Van Caenegem, Lea Arti, Thibaut Troupel, Aurelien Jeandel, Helene Vandenberghe, Vincent Mayousse, Stella Papageorgiou, Kirsten Gnirs, Stephane Blot
Summary: This study aimed to refine the clinical description and classification of immune-mediated polyneuropathy in cats. Results showed good prognosis and proposed diagnostic criteria for this condition.
JOURNAL OF VETERINARY INTERNAL MEDICINE
(2023)
Article
Cell Biology
Flavien Bizot, Abdallah Fayssoil, Cecile Gastaldi, Tabitha Irawan, Xaysongkhame Phongsavanh, Arnaud Mansart, Thomas Tensorer, Elise Brisebard, Luis Garcia, Rudolph L. Juliano, Aurelie Goyenvalle
Summary: Nucleic acid-based therapeutics show promise for treating diseases like DMD, but face challenges like poor drug distribution and entrapment in the endosomal compartment. Oligonucleotide-enhancing compounds (OEC) can help release drugs and improve nuclear concentration, enhancing the therapeutic potential of exon-skipping approaches. This study demonstrates the potential of a combination therapy involving ASO and OEC for the treatment of DMD.
Article
Cardiac & Cardiovascular Systems
Bijan Ghaleh, Ines Barthelemy, Lucien Sambin, Alain Bize, Daphne Corboz, Luc Hittinger, Stephane Blot, Jin Bo Su
Summary: The study used two-dimensional speckle tracking echocardiography to analyze the non-uniformity of myocardial strain in golden retriever muscular dystrophy (GRMD) dogs. The results showed spatial and temporal heterogeneity in the myocardial strain, providing new insights into the progression of dystrophin-deficient cardiomyopathy.
JOURNAL OF CARDIOVASCULAR DEVELOPMENT AND DISEASE
(2023)
Article
Biochemistry & Molecular Biology
Flavien Bizot, Thomas Tensorer, Luis Garcia, Aurelie Goyenvalle
Summary: Preventing renal clearance of ASO using an OAT inhibitor does not improve the therapeutic potential of ASO-mediated exon-skipping approaches for the treatment of DMD.
NUCLEIC ACID THERAPEUTICS
(2023)