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
Biochemistry & Molecular Biology
Yusuke Echigoya, Nhu Trieu, William Duddy, Hong M. Moulton, HaiFang Yin, Terence A. Partridge, Eric P. Hoffman, Joe N. Kornegay, Frank A. Rohret, Christopher S. Rogers, Toshifumi Yokota
Summary: Duchenne muscular dystrophy (DMD) is a lethal genetic disorder caused by mutations in the DMD gene. Although PMO-ASOs have been approved for clinical use, their applicability remains limited. Establishing a DMD large animal model is crucial for evaluating treatment efficacy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biotechnology & Applied Microbiology
Nalinda B. Wasala, Yongping Yue, Bryan Hu, Jin-Hong Shin, Gang Yao, Dongsheng Duan
Summary: In this study, the researchers injected the AAV mu Dys vector into mdx mice and observed significant improvements in muscle strength, exercise capacity, and cardiac function. The results suggest that AAV mu Dys therapy has the potential to provide lifelong benefits in patients with Duchenne muscular dystrophy.
HUMAN GENE THERAPY
(2023)
Article
Multidisciplinary Sciences
Shuaiwei Ren, Mei Huang, Raoxian Bai, Lijiao Chen, Jiao Yang, Junyu Zhang, Wenting Guo, Weizhi Ji, Yongchang Chen
Summary: This study demonstrates that antisense circular RNAs (AS-circRNAs) can effectively mediate exon skipping and correct the open reading frame in a mouse model of DMD. AS-circRNAs specifically target the precursor mRNA splicing without off-target effects and may serve as a novel tool for genetic disease treatment.
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
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
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
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
Loren L. Flynn, Chalermchai Mitrpant, Abbie Adams, Ianthe L. Pitout, Anja Stirnweiss, Sue Fletcher, Steve D. Wilton
Summary: The use of antisense oligonucleotides in disease treatment is expanding, with improvements in chemistry enhancing their stability and effectiveness. Rational sequence design and chemistry optimization are crucial for ensuring antisense activity.
Article
Pathology
Alexandra Monceau, Dylan Moutachi, Megane Lemaitre, Luis Garcia, Capucine Trollet, Denis Furling, Arnaud Klein, Arnaud Ferry
Summary: This study evaluated the impact of voluntary exercise on gene therapy exon skipping approach in a severe DMD murine model. The results showed that voluntary running did not induce muscle damage and did not have a drastic detrimental effect on the gene therapy method. Moreover, these findings suggest considering exercise as an additional factor in future therapeutic approaches for DMD.
AMERICAN JOURNAL OF PATHOLOGY
(2022)
Article
Chemistry, Medicinal
Michaella Georgiadou, Melina Christou, Kleitos Sokratous, Jesper Wengel, Kyriaki Michailidou, Kyriacos Kyriacou, Andrie Koutsoulidou, Nikolaos P. Mastroyiannopoulos, Leonidas A. Phylactou
Summary: Duchenne muscular dystrophy (DMD) is a fatal disorder characterized by progressive muscle wasting caused by mutations in the dystrophin gene. Antisense oligonucleotide (AON)-mediated skipping of the mutated exon, especially using LNA/2’OMe AONs, has shown significant potential in inducing exon skipping and dystrophin restoration in treated muscles, paving the way for further therapeutic experimentation.
Article
Biochemistry & Molecular Biology
Kazuhiro Maeta, Manal Farea, Hisahide Nishio, Masafumi Matsuo
Summary: This study identified a novel antisense oligonucleotide called KMM001 that inhibits the maturation of myostatin mRNA, resulting in decreased myostatin protein levels. KMM001 also inhibits SMAD-mediated myostatin signaling and promotes human myoblast proliferation. These findings suggest that KMM001 has potential therapeutic applications for muscle-wasting conditions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
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
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
Cell Biology
Tetsuaki Hiyoshi, Fuqiang Zhao, Rina Baba, Takeshi Hirakawa, Ryosuke Kuboki, Kazunori Suzuki, Yoshiro Tomimatsu, Patricio ODonnell, Steve Han, Neta Zach, Masato Nakashima
Summary: This study investigated the potential of electrical impedance myography (EIM) as a biomarker for Duchenne muscular dystrophy (DMD). The findings showed that EIM could be used to monitor changes in skeletal muscle composition and detect dystrophin-related muscle abnormalities. Furthermore, EIM reactance had the potential to monitor the recovery of muscle abnormalities in response to antisense-mediated exon skipping.
Article
Biochemistry & Molecular Biology
Alberto Malerba, Fanny Roth, Pradeep Harish, Jamila Dhiab, Ngoc Lu-Nguyen, Ornella Cappellari, Susan Jarmin, Alexandrine Mahoudeau, Victor Ythier, Jeanne Laine, Elisa Negroni, Emmanuelle Abgueguen, Martine Simonelig, Philippe Guedat, Vincent Mouly, Gillian Butler-Browne, Cecile Voisset, George Dickson, Capucine Trollet
HUMAN MOLECULAR GENETICS
(2019)
Article
Geriatrics & Gerontology
Pradeep Harish, Alberto Malerba, Ngoc Lu-Nguyen, Leysa Forrest, Ornella Cappellari, Fanny Roth, Capucine Trollet, Linda Popplewell, George Dickson
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE
(2019)
Article
Biochemistry & Molecular Biology
Alberto Malerba, Pierre Klein, Ngoc Lu-Nguyen, Ornella Cappellari, Vanessa Strings-Ufombah, Sonal Harbaran, Peter Roelvink, David Suhy, Capucine Trollet, George Dickson
HUMAN MOLECULAR GENETICS
(2019)
Article
Biochemistry & Molecular Biology
Ngoc Lu-Nguyen, Arnaud Ferry, Frederick J. Schnell, Gunnar J. Hanson, Linda Popplewell, George Dickson, Alberto Malerba
HUMAN MOLECULAR GENETICS
(2019)
Article
Geriatrics & Gerontology
Haiyan Zhou, Jinhong Meng, Alberto Malerba, Francesco Catapano, Palittiya Sintusek, Susan Jarmin, Lucy Feng, Ngoc Lu-Nguyen, Lianwen Sun, Virginie Mariot, Julie Dumonceaux, Jennifer E. Morgan, Paul Gissen, George Dickson, Francesco Muntoni
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE
(2020)
Article
Biochemistry & Molecular Biology
Lukasz Ciszewski, Ngoc Lu-Nguyen, Alex Slater, Andrew Brennan, Huw E. L. Williams, George Dickson, Mark S. Searle, Linda Popplewell
NUCLEIC ACIDS RESEARCH
(2020)
Article
Biotechnology & Applied Microbiology
Alberto Malerba, Chiara Sidoli, Ngoc Lu-Nguyen, Shan Herath, Anita Le Heron, Hayder Abdul-Razak, Susan Jarmin, Thierry VandenDriessche, Marinee K. Chuah, George Dickson, Linda Popplewell
Summary: Duchenne muscular dystrophy (DMD) is a genetic disease affecting male individuals, with no cure currently available. Gene therapy, particularly using AAV vectors, shows promise in improving expression levels and relieving symptoms in patients.
HUMAN GENE THERAPY
(2021)
Article
Biochemistry & Molecular Biology
Ngoc Lu-Nguyen, Alberto Malerba, Shan Herath, George Dickson, Linda Popplewell
Summary: Aberrant expression of the DUX4 gene in skeletal muscle causes muscle deterioration in FSHD. Disrupting the polyadenylation signal can prevent its expression. Using antisense approaches to reduce DUX4 expression has shown promising results in improving muscle pathology and strength.
HUMAN MOLECULAR GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Betty R. Kao, Alberto Malerba, Ngoc B. Lu-Nguyen, Pradeep Harish, John J. McCarthy, George Dickson, Linda J. Popplewell
Summary: The study found that downregulation of RPL3L in healthy and dystrophic mice can enhance muscle function and improve resistance to muscle damage. Additionally, inhibition of RPL3L resulted in a significant increase in muscle length and a decrease in cross-sectional area, suggesting that this ribosomal protein may play a role in myofiber morphology.
NUCLEIC ACID THERAPEUTICS
(2021)
Article
Medicine, Research & Experimental
Vanessa Strings-Ufombah, Alberto Malerba, Shih-Chu Kao, Sonal Harbaran, Fanny Roth, Ornella Cappellari, Ngoc Lu-Nguyen, Keiko Takahashi, Sophie Mukadam, Georgina Kilfoil, Claudia Kloth, Petrus Roelvink, George Dickson, Capucine Trollet, David Suhy
Summary: The study demonstrates a promising therapeutic strategy for OPMD by delivering silence and replace sequences in a single AAV vector, resulting in robust inhibition of mutant PABPN1 and concomitant replacement of the codon-optimized PABPN1 protein, leading to restoration of muscle strength and other physiological improvements in a mouse model of the disease.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2021)
Article
Biotechnology & Applied Microbiology
Ngoc Lu-Nguyen, Alberto Malerba, Marina Antoni Pineda, George Dickson, Linda Popplewell
Summary: Facioscapulohumeral muscular dystrophy (FSHD) is a rare muscle dystrophy that initially affects the muscles in the face, shoulders, and upper arms, but progresses to lower body muscles. The respiratory restriction in FSHD is more common and severe than previously thought, and the involvement of diaphragm weakness in pulmonary insufficiency is debated. This study shows that suppressing the expression of the DUX4 gene can improve muscle regeneration and prevent muscle fibrosis in FSHD, suggesting its potential as a treatment for the disease.
HUMAN GENE THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Ngoc Lu-Nguyen, George Dickson, Alberto Malerba, Linda Popplewell
Summary: The study demonstrated the efficacy of vivoPMO-PACS4 in treating FSHD by using a more suitable model that mimics the clinical condition. The treatment resulted in significant improvements in muscle mass and strength, as well as reductions in myofiber central nucleation and muscle fibrosis.
Article
Biochemistry & Molecular Biology
Viktorija Cernisova, Ngoc Lu-Nguyen, Jessica Trundle, Shan Herath, Alberto Malerba, Linda Popplewell
Summary: Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease that primarily affects newborn males. Gene addition therapy using adeno-associated viral vectors has shown significant improvement in muscle function and prevention of fibrosis in a relevant animal model of DMD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Jamuna Selvakumaran, Simona Ursu, Melissa Bowerman, Ngoc Lu-Nguyen, Matthew J. Wood, Alberto Malerba, Rafael J. Yanez-Munoz
Summary: The blood-brain barrier (BBB) is a specialized microvasculature system that protects the central nervous system (CNS) from toxic agents. Researchers have successfully differentiated induced pluripotent stem cells (iPSC) into brain microvascular endothelial cells (BMECs) to create a human BBB model. This model demonstrates tight barrier properties and can be used to evaluate drug penetration into the CNS.
Meeting Abstract
Biotechnology & Applied Microbiology
V. Cernisova, G. Golshirazi, C. Chi, B. Zhang, A. Malerba, N. Lu-Nguyen, L. Popplewell
HUMAN GENE THERAPY
(2019)