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
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
Remko Goossens, Nisha Verwey, Yavuz Ariyurek, Fred Schnell, Annemieke Aartsma-Rus
Summary: The study reveals that the non-sequential splicing of DMD transcript and the retention time of adjacent introns have an impact on the efficiency of AON. Targeting an out-of-frame exon flanked by a "slow" intron at its 5'-end leads to higher exon skipping efficiency. Furthermore, placing AON closer to the 5'-end of the target exon results in better skipping efficiency regardless of the splicing speed of adjacent introns.
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
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
Biology
Shalini Gupta, Swrajit Nath Sharma, Jayanta Kundu, Sankha Pattanayak, Surajit Sinha
Summary: This review provides a detailed account of the evolution of phosphorodiamidate morpholino oligonucleotides (PMOs) in exon skipping therapy for Duchenne muscular dystrophy (DMD) over the past two decades. It discusses the structural and functional advancements of PMOs and the challenges that still need to be overcome, particularly in restoring dystrophin in cardiac muscle. The review also presents the current scenario and future perspectives for improving PMOs and revolutionizing therapeutic benefits in DMD.
JOURNAL OF BIOSCIENCES
(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
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
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
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
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
Biochemistry & Molecular Biology
Elena Marchesi, Rita Cortesi, Lorenzo Preti, Paola Rimessi, Maddalena Sguizzato, Matteo Bovolenta, Daniela Perrone
Summary: This study explored the influence of lipophilic moiety on exon skipping efficiency of ASO 51 and designed a series of lipophilic conjugates. The stability of conjugates with target RNA was evaluated by measuring the melting temperature, and the exon skipping efficiency was assessed in the presence and absence of a transfection agent. The results showed that 5'-UDC- and 5',3'-bis-UDC-ASO 51 were the most efficient compounds for exon skipping.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Mathematical & Computational Biology
Renee X. de Menezes, Armin Rauschenberger, Bios Consortium, Peter A. C. 't Hoen, Marianne A. Jonker
Summary: This article introduces a score-based test method that takes into account the effects of all exons and all SNPs on exon inclusion simultaneously. The test method is computationally efficient and can be used when the number of SNPs is larger than the number of samples. It is also more robust to exon-SNP pair-specific effects.
BIOMETRICAL JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
Sarah Engelbeen, Svetlana Pasteuning-Vuhman, Joke Boertje-van der Meulen, Rubina Parmar, Klaus Charisse, Laura Sepp-Lorenzino, Muthiah Manoharan, Annemieke Aartsma-Rus, Maaike van Putten
Summary: This study investigates the therapeutic effect of chemically modified siRNA delivery targeting the Alk4 gene, demonstrating it can effectively suppress the expression of Alk4 in muscles, with potential clinical implications for the treatment of muscular dystrophy.
NUCLEIC ACID THERAPEUTICS
(2023)
Editorial Material
Genetics & Heredity
Jerry Vockley, Annemieke Aartsma-Rus, Jennifer L. Cohen, Lex M. Cowsert, R. Rodney Howell, Timothy W. Yu, Melissa P. Wasserstein, Thomas Defay
Summary: Rare genetic disorders affect a certain percentage of newborn babies, and early diagnosis and treatment are challenging. The advancement of whole-genome sequencing (WGS) technology provides the possibility of early diagnosis and opens up new avenues for the treatment of rare genetic disorders. However, there are still several challenges to overcome. This article summarizes the impact of WGS on the diagnosis and treatment of rare genetic disorders.
AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS
(2023)
Article
Medicine, General & Internal
Remco T. P. van Cruchten, Daniel van As, Jeffrey C. Glennon, Baziel G. M. van Engelen, Peter A. C. 't Hoen
Summary: This study identified druggable molecular biomarkers associated with the clinical improvement in DM1 patients receiving cognitive behavioral therapy (CBT), providing potential targets for drug discovery and therapy efficacy assessments.
Article
Biotechnology & Applied Microbiology
Galina Filonova, Annemieke Aartsma-Rus
Summary: The exon-skipping approach is a potential therapy for Duchenne muscular dystrophy (DMD) patients, but the current levels of dystrophin restoration are low. Efforts are being made to improve the efficiency of exon skipping through chemical modifications of antisense oligonucleotides (AONs). Several approved and newly developed AONs are under preclinical and clinical investigation for their safety and effectiveness.
EXPERT OPINION ON BIOLOGICAL THERAPY
(2023)
Editorial Material
Biochemistry & Molecular Biology
Annemieke Aartsma-Rus, Willeke van Roon-Mom, Marlen Lauffer, Christine Siezen, Britt Duijndam, Tineke Coenen-de Roo, Rebecca Schuele, Matthis Synofzik, Holm Graessner
Summary: Splice-modulating antisense oligonucleotides (ASOs) provide treatment options for rare neurological diseases with rare mutations, and patient-specific ASOs need to be developed. The 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop and treat eligible patients with patient-specific ASOs in Europe and the Netherlands, respectively, under a named patient setting.
Article
Biochemistry & Molecular Biology
Annemieke Aartsma-Rus, Alejandro Garanto, Willeke Van Roon-Mom, Erin M. McConnell, Victoria Suslovitch, Winston X. Yan, Jonathan K. Watts, Timothy W. Yu
Summary: The N = 1 Collaborative (N1C) recently organized a workshop to discuss and advance standards for the design and testing of splice-switching ASOs for individualized medicine. In this study, guidelines are presented, including the dissemination of standardized experimental designs, use of standardized reference ASOs, and a commitment to data sharing and exchange.
NUCLEIC ACID THERAPEUTICS
(2023)
Article
Biology
Tooba Abbassi-Daloii, Salma el Abdellaoui, Lenard M. Voortman, Thom T. J. Veeger, Davy Cats, Hailiang Mei, Duncan E. Meuffels, Ewoud van Arkel, Peter Bram 't Hoen, Hermien Kan, Vered Raz
Summary: We constructed a large atlas of RNA-seq profiles from leg muscles, identifying differential expression patterns and cellular composition across different tissues. The muscle samples were clustered into three groups based on anatomical location, which were associated with oxidative metabolism and fast- or slow-twitch myofibers. Expression profiles of Homeobox transcription factors differed between the three groups. Our study provides a novel resource to study muscle-specific molecular features and their potential links to physiological processes.
Article
Biotechnology & Applied Microbiology
Annemieke Aartsma-Rus
Summary: Antisense oligonucleotide (ASO)-mediated exon skipping can restore the open reading frame of dystrophin transcripts for Duchenne muscular dystrophy (DMD) patients. Ways to improve ASO efficiency and applicability of this mutation-specific approach are evaluated in this expert perspective.
HUMAN GENE THERAPY
(2023)
Article
Multidisciplinary Sciences
Mirko Signorelli, Roula Tsonaka, Annemieke Aartsma-Rus, Pietro Spitali
Summary: Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by a lack of dystrophin in skeletal muscle. To better understand the disease progression and response to therapy, a study analyzed longitudinal multiomic data from 3 murine models of DMD. Integration of RNA-seq, metabolomic, and lipidomic data revealed 8 latent factors that explained a large portion of the variance in the dataset. These factors could distinguish between healthy and dystrophic mice, as well as different time-points. The study also connected gene expression changes in dystrophic muscles to inflammation and lipid signatures in the blood.
Article
Biochemistry & Molecular Biology
Remko Goossens, Nisha Verwey, Yavuz Ariyurek, Fred Schnell, Annemieke Aartsma-Rus
Summary: The study reveals that the non-sequential splicing of DMD transcript and the retention time of adjacent introns have an impact on the efficiency of AON. Targeting an out-of-frame exon flanked by a "slow" intron at its 5'-end leads to higher exon skipping efficiency. Furthermore, placing AON closer to the 5'-end of the target exon results in better skipping efficiency regardless of the splicing speed of adjacent introns.
Article
Multidisciplinary Sciences
L. G. M. Heezen, T. Abdelaal, M. van Putten, A. Aartsma-Rus, A. Mahfouz, P. Spitali
Summary: Using spatial transcriptomics, the authors identified gene expression signatures related to the histopathological changes in Duchenne mouse models. This study provides valuable insights into the underlying pathology and potential therapeutic targets for Duchenne muscular dystrophy.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Willeke van Roon-Mom, Chantal Ferguson, Annemieke Aartsma-Rus
NUCLEIC ACID THERAPEUTICS
(2023)
Article
Biochemistry & Molecular Biology
Sarah Engelbeen, Daniel O'Reilly, Davy van de Vijver, Ingrid Verhaart, Maaike van Putten, Vignesh Hariharan, Matthew Hassler, Anastasia Khvorova, Masad J. Damha, Annemieke Aartsma-Rus
Summary: In this study, the researchers aimed to optimize the efficiency of antisense oligonucleotide (AON) therapy for Duchenne muscular dystrophy (DMD) patients. They evaluated exon 53 skipping of the DMD transcript with different chemically modified AONs and found that FRNA, LNA-FRNA, and LNA-2'O-Me AONs were the most efficient in human control myoblast cultures. However, in a mouse experiment, treatment with LNA-FRNA and LNA-2'O-Me AONs resulted in high levels of exon 53 skipping but no restoration of dystrophin, mainly due to the strong binding nature of LNA modifications to RNA interfering with amplification of unskipped product.
NUCLEIC ACID THERAPEUTICS
(2023)
Article
Medicine, Research & Experimental
Yu C. J. Chey, Jayshen Arudkumar, Annemieke Aartsma-Rus, Fatwa Adikusuma, Paul Q. Thomas
Summary: CRISPR gene-editing technology allows for the generation of animal disease models and has the potential to revolutionize the treatment of genetic disorders, such as Duchenne muscular dystrophy. It enables the generation of animal models that closely simulate disease-causing mutations, providing a platform for testing interventions like CRISPR therapy.
WIRES MECHANISMS OF DISEASE
(2023)