Review
Biochemistry & Molecular Biology
Britt Hanson, Matthew J. A. Wood, Thomas C. Roberts
Summary: Duchenne muscular dystrophy (DMD) is an incurable genetic muscle disorder characterized by muscle wasting and premature death, with therapeutic approaches including antisense oligonucleotide-mediated splice modulation and gene editing. Progress has been made in the treatment of DMD, but challenges and limitations remain in clinical translation.
Article
Chemistry, Multidisciplinary
Bao T. Le, Sudhir Agarwal, Rakesh N. Veedu
Summary: This study evaluated the potential of incorporating DNA segments at appropriate sites in 2'-OMe PS and 2'-MOE PS ASOs to induce exon skipping. The results demonstrated that 2'-modified RNA PS ASOs containing four or less PS DNA nucleotides at the 3'-end yielded improved exon 23 skipping efficacy, opening new avenues towards designing splice modulating ASOs with limited chemical modifications for enhanced safety and therapeutic efficacy.
Article
Biochemistry & Molecular Biology
Pachamuthu Kandasamy, Graham McClorey, Mamoru Shimizu, Nayantara Kothari, Rowshon Alam, Naoki Iwamoto, Jayakanthan Kumarasamy, Gopal R. Bommineni, Adam Bezigian, Onanong Chivatakarn, David C. D. Butler, Michael Byrne, Katarzyna Chwalenia, Kay E. Davies, Jigar Desai, Juili Dilip Shelke, Ann F. Durbin, Ruth Ellerington, Ben Edwards, Jack Godfrey, Andrew Hoss, Fangjun Liu, Kenneth Longo, Genliang Lu, Subramanian Marappan, Jacopo Oieni, Ik-Hyeon Paik, Erin Purcell Estabrook, Chikdu Shivalila, Maeve Tischbein, Tomomi Kawamoto, Carlo Rinaldi, Joana Rajao-Saraiva, Snehlata Tripathi, Hailin Yang, Yuan Yin, Xiansi Zhao, Cong Zhou, Jason Zhang, Luciano Apponi, Matthew J. A. Wood, Chandra Vargeese
Summary: By engineering chimeric stereopure oligonucleotides, significant improvements in pharmacology and efficacy have been achieved, leading to an extended median survival in a mouse model of muscular dystrophy.
NUCLEIC ACIDS RESEARCH
(2022)
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
Cell Biology
Dhanu Gupta, Sara Orehek, Janne Turunen, Liz O'Donovan, Michael J. Gait, Samir El-Andaloussi, Matthew J. A. Wood
Summary: Interleukin-6 (IL-6) plays an important role in inflammatory and autoimmune diseases. Recent research has found that trans-signaling of IL-6 is crucial for its anti-inflammatory effects. This study developed a novel approach to specifically target IL-6 trans-signaling by modulating alternative splicing in the GP130 protein, resulting in truncated soluble isoforms that can sequester IL-6 and its receptor complex, effectively reducing inflammation in mouse models. This gene therapy platform shows promising potential for treating chronic inflammatory diseases.
Article
Biochemistry & Molecular Biology
Caorui Lin, Gang Han, Lulu Jia, Yiwen Zhao, Jun Song, Ning Ran, Toshifumi Yokota, Yiqi Seow, HaiFang Yin
Summary: This study demonstrates that the combination of oral glycine and metformin with intravenous PMO can enhance the efficacy of PMO treatment for DMD. This combination therapy shows potential benefits for DMD patients and potentially other muscle diseases.
Article
Hematology
Alisa Dong, Valentina Ghiaccio, Irene Motta, Shuling Guo, Raechel Peralta, Susan M. Freier, Andy Watt, Sagar Damle, Yasuhiro Ikawa, Danuta Jarocha, Maxwell Chappell, Coralea Stephanou, Paola Delbini, Connie Chen, Soteroula Christou, Marina Kleanthous, Kim Smith-Whitley, Deepa Manwani, Carla Casu, Osheiza Abdulmalik, Maria Domenica Cappellini, Stefano Rivella, Laura Breda
Summary: Beta-thalassemia is a global disorder that requires alternative treatment strategies due to limited options currently available. Aberrant splicing is one of the processes that affects beta-globin synthesis in patients with beta-thalassemia.
Article
Chemistry, Medicinal
Warren C. Chan, Kelsey A. Trieger, James J. La Clair, Catriona H. M. Jamieson, Michael D. Burkart
Summary: Highly functionalized skeletons of macrolide natural products provide rare atomic arrangements, where stereochemistry changes have significant impact on structure and function. Spliceosome modulators have a unique consensus motif, mainly targeting the SF3B spliceosome complex interface. Our recent synthetic campaign of 17S-FD-895 provides stereochemical analogues of this complex macrolide. In this study, we report the preparation and systematic activity evaluation of multiple FD-895 analogues, exploring the effects of modifications at specific stereocenters and suggesting future directions for medicinal chemical optimization of spliceosome modulators.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Letter
Medicine, General & Internal
Carsten G. Boennemann, Beth A. Belluscio, Serge Braun, Carl Morris, Teji Singh, Francesco Muntoni
Summary: Five boys with Duchenne's muscular dystrophy received gene therapy using three different AAV products. However, they experienced serious adverse reactions and laboratory findings indicated cytotoxic T-cell immune responses.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Article
Medicine, Research & Experimental
Li Gan, Leslie C. L. Wu, Jenna A. Wood, Monica Yao, Chris M. Treleaven, Nelsa L. Estrella, Bruce M. Wentworth, Gunnar J. Hanson, Marco A. Passini
Summary: Antisense RNA technology is a strategy for treating Duchenne muscular dystrophy (DMD) by promoting exon skipping and producing functional dystrophin protein. Peptide-conjugated PMOs (PPMOs) are a next-generation platform that enhances cellular uptake. RC-1001, a PPMO, demonstrated increased exon skipping, dystrophin production, and improved muscle function in mdx mice. These findings support the clinical development of PPMO therapies for DMD.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Article
Oncology
Wai Kit Ma, Dillon M. Voss, Juergen Scharner, Ana S. H. Costa, Kuan-Ting Lin, Hyun Yong Jeon, John E. Wilkinson, Michaela Jackson, Frank Rigo, C. Frank Bennett, Adrian R. Krainer
Summary: The upregulation of the M2 pyruvate kinase (PKM2) isoform in most cancers, which is involved in the Warburg effect, can be inhibited by antisense oligonucleotides (ASO), leading to apoptosis in liver cancer cells. This ASO-based splicing therapy shows potential as a targeted treatment for hepatocellular carcinoma (HCC) by altering glucose metabolism and inhibiting tumor growth.
Article
Multidisciplinary Sciences
Wren E. Michaels, Cecilia Pena-Rasgado, Rusudan Kotaria, Robert J. Bridges, Michelle L. Hastings
Summary: Mutations in the CFTR gene result in cystic fibrosis, and skipping exon 23 can partially restore CFTR function, showing therapeutic potential for CF treatment.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Muhammad Dain Yazid, Chen Hung-Chih
Summary: This study utilized a dystrophin-deficient myoblast model and found that disruption of the PTEN-PI3K/Akt pathway leads to excessive autophagosome formation and reduced autophagic flux, providing insights into the pathogenesis of Duchenne Muscular Dystrophy (DMD). It is believed that manipulation within this signaling pathway could potentially help restore muscle homeostasis and slow down disease progression.
CELL COMMUNICATION AND SIGNALING
(2021)
Review
Biochemistry & Molecular Biology
Florian Malard, Cameron D. Mackereth, Sebastien Campagne
Summary: This article discusses the early stage of spliceosome assembly in eukaryotes, focusing on the factors that influence U1 snRNP's selection of splice sites in pre-mRNA. It also includes examples of diseases that affect this selection and recent therapeutic advances.
Review
Clinical Neurology
Katharina E. Meijboom, Robert H. Brown
Summary: Researchers have made new progress in the treatment of amyotrophic lateral sclerosis (ALS), including innovative applications and clinical trials of gene modulation therapies. By using adeno-associated virus (AAV)-mediated microRNAs and antisense oligonucleotides (ASOs) to target gain-of-function pathology of common ALS genes, these methods have the potential to positively impact future ALS treatments.
Article
Biochemistry & Molecular Biology
Annemieke Aartsma-Rus, Elizabeth Vroom, Daniel O'Reilly
Summary: The involvement of patients and patient representatives is crucial in the drug development process, as they can provide valuable insights into symptom burdens and key benefits. Success factors include finding the right partners, bilateral education, and maintaining realistic expectations.
NUCLEIC ACID THERAPEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Matthis Synofzik, Willeke M. C. Van Roon-Mom, Georg Marckmann, Hermine A. van Duyvenvoorde, Holm Graessner, Rebecca Schule, Annemieke Aartsma-Rus
Summary: ASO therapies offer a promising disease-modifying approach for rare neurological diseases, but there is a need to focus on ultrarare or private variants to provide treatment for a larger share of patients. The emerging field of n-of-1 ASO treatment approaches requires systematic guidance and standards to allow global scaling, particularly in the European context. Genetic, regulatory, and ethical perspectives are essential for preparing and implementing n-of-1 ASO treatments to ensure both individual patient benefit and knowledge gain.
NUCLEIC ACID THERAPEUTICS
(2022)
Letter
Cardiac & Cardiovascular Systems
Dongsheng Duan, Kevin M. Flanigan, Annemieke Aartsma-Rus
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
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
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)
