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
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
Biotechnology & Applied Microbiology
Liubov V. Gushchina, Emma C. Frair, Natalie Rohan, Adrienne J. Bradley, Tabatha R. Simmons, Hemantkumar D. Chavan, Hsin-Jung Chou, Michelle Eggers, Megan A. Waldrop, Nicolas Wein, Kevin M. Flanigan
Summary: The study focuses on the preclinical development of an AAV-encapsidated viral vector containing U7snRNA targeting specific sites of DMD exon 2. Findings from a dose escalation toxicity study in nonhuman primates showed no significant toxicity, supporting the safety of the approach for a first-in-human clinical trial.
HUMAN GENE THERAPY
(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
Biotechnology & Applied Microbiology
Nicolas Wein, Diane M. Dunn, Megan A. Waldrop, Liubov Gushchina, Emma C. Frair, Robert B. Weiss, Kevin M. Flanigan
Summary: Exon skipping therapies for Duchenne muscular dystrophy can be induced by modified U7snRNA delivered by an AAV vector, resulting in highly efficient exclusion of targeted exons. The study demonstrated the specificity and effectiveness of this approach in correcting gene expression errors, with minimal off-target splicing effects detected through RNA-seq analysis.
HUMAN GENE THERAPY
(2021)
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
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
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
Clinical Neurology
Giulio Gadaleta, Guido Urbano, Chiara Brusa, Rossella D'Alessandro, Enrica Rolle, Ilaria Cavallina, Alessio Mattei, Fulvia Ribolla, Claudia Raineri, Stefano Pidello, Liliana Vercelli, Federica S. Ricci, Tiziana E. Mongini
Summary: The clinical characteristics of adults with DMD include mechanical ventilation, swallowing and nutritional issues, and bone density alterations. Other issues include respiratory infections, gastrointestinal symptoms, metabolic acidosis, psychiatric symptoms, and chronic pain. Patients have a negative perception of their physical health but a more positive assessment of their mental health.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Pharmacology & Pharmacy
Zeren Sun, Dengqiu Xu, Lei Zhao, Xihua Li, Sijia Li, Xiaofei Huang, Chunjie Li, Lixin Sun, Bing Liu, Zhenzhou Jiang, Luyong Zhang
Summary: The study found that fenofibrate can promote the differentiation of myofibers by down-regulating the expression of myostatin protein in myoblasts, significantly improving muscle function and reducing muscle damage in mdx mice, along with anti-inflammatory effects.
BRITISH JOURNAL OF PHARMACOLOGY
(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
Clinical Neurology
Craig M. Zaidman, Crystal M. Proud, Craig M. Mcdonald, Kelly J. Lehman, Natalie L. Goedeker, Stefanie Mason, Alexander P. Murphy, Maitea Guridi, Shufang Wang, Carol Reid, Eddie Darton, Christoph Wandel, Sarah Lewis, Jyoti Malhotra, Danielle A. Griffin, Rachael A. Potter, Louise R. Rodino-Klapac, Jerry R. Mendell
Summary: The study ENDEAVOR demonstrated that the commercial process delandistrogene moxeparvovec is safe and effective in improving micro-dystrophin expression in patients with Duchenne muscular dystrophy. After 12 weeks of treatment, significant improvements were observed in micro-dystrophin expression, as well as patient's functional outcomes and quality of life at 1 year.
ANNALS OF NEUROLOGY
(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)
Review
Cell Biology
Elisa Domi, Malvina Hoxha, Emanuela Prendi, Bruno Zappacosta
Summary: Duchenne muscular dystrophy is a muscular disease with no cure, and SIRT1 has been identified as a potential therapeutic target for the condition. Activation of SIRT1 improves muscle function, while its inhibition leads to muscle fragility.
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)
Editorial Material
Multidisciplinary Sciences
Alessandra Ferlini, Aurelie Goyenvalle, Francesco Muntoni
Correction
Genetics & Heredity
Simon Krooss, Sonja Werwitzke, Johannes Kopp, Alice Rovai, Dirk Varnholt, Amelie S. Wachs, Aurelie Goyenvalle, Annemieke Aartsma-Rus, Michael Ott, Andreas Tiede, Jorg Langemeier, Jens Bohne
Review
Medicine, Research & Experimental
Suzan M. Hammond, Annemieke Aartsma-Rus, Sandra Alves, Sven E. Borgos, Ronald A. M. Buijsen, Rob W. J. Collin, Giuseppina Covello, Michela A. Denti, Lourdes R. Desviat, Lucia Echevarria, Camilla Foged, Gisela Gaina, Alejandro Garanto, Aurelie T. Goyenvalle, Magdalena Guzowska, Irina Holodnuka, David R. Jones, Sabine Krause, Taavi Lehto, Marisol Montolio, Willeke Van Roon-Mom, Virginia Arechavala-Gomeza
Summary: The field of nucleic acid-based therapeutics has seen rapid development in recent years, with the main challenge being delivery to target tissues. The adoption of delivery technologies, such as conjugates or nanoparticles, has been a game changer for many therapeutic indications.
EMBO MOLECULAR MEDICINE
(2021)
Article
Neurosciences
Mirella Telles Salgueiro Barboni, Andre Mauricio Passos Liber, Anneka Joachimsthaler, Amel Saoudi, Aurelie Goyenvalle, Alvaro Rendon, Jerome E. Roger, Dora Fix Ventura, Jan Kremers, Cyrille Vaillend
Summary: The mdx52 mouse model of Duchenne muscular dystrophy lacks exon 52 of the DMD gene, which leads to the loss of certain dystrophin proteins and visual abnormalities. In this study, mdx52 mice showed reduced amplitudes and delayed implicit times in their ERG responses, as well as diminished responses to various stimuli in both dark-adapted and light-adapted conditions. Their contrast sensitivity was also significantly reduced at 50% contrast. These findings suggest that the mdx52 mouse model may be useful for studying retinal dystrophins and related preclinical studies on DMD.
NEUROBIOLOGY OF DISEASE
(2021)
Review
Medicine, Research & Experimental
Amel Saoudi, Aurelie Goyenvalle
Summary: Advances in genetic and genomic research have led to a better understanding of hereditary diseases attributed to aberrant splicing, making them ideal targets for RNA modulation therapies. Novel strategies like exon skipping or re-inclusion during splicing have shown promise in the clinic, particularly in treating neuromuscular diseases. Further research into improving the biodistribution of antisense oligonucleotides and exploring alternative chemistries or delivery systems is ongoing to overcome current limitations in splicing therapies.
M S-MEDECINE SCIENCES
(2021)
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)
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
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
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
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
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)
Article
Cell Biology
Amel Saoudi, Faouzi Zarrouki, Catherine Sebrie, Charlotte Izabelle, Aure'lie Goyenvalle, Cyrille Vaillend
Summary: The exon-52-deleted mdx52 mouse model is critical for studying DMD, showing no gross brain abnormalities but significant behavioral phenotypes like enhanced anxiety and impaired Pavlovian association, similar to problems reported in some DMD patients. These findings suggest the potential of using mdx52 mice for preclinical evaluation of treatments targeting brain dysfunctions in DMD.
DISEASE MODELS & MECHANISMS
(2021)