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)
Review
Biochemistry & Molecular Biology
Franciscus C. Vermeer, Jeroen Bremer, Robert J. Sietsma, Aileen Sandilands, Robyn P. Hickerson, Marieke C. Bolling, Anna M. G. Pasmooij, Henny H. Lemmink, Morris A. Swertz, Nine V. A. M. Knoers, K. Joeri van der Velde, Peter C. van den Akker
Summary: Epidermolysis bullosa is a genetic skin condition characterized by skin fragility caused by gene variants, with treatment currently focused on symptom relief. Exon skipping shows potential as a therapeutic strategy for EB, with the severity of the disease linked to gene involvement and variants.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Young Jin Kim, Nicole Sivetz, Jessica Layne, Dillon M. Voss, Lucia Yang, Qian Zhang, Adrian R. Krainer
Summary: Mutations in the CFTR gene cause cystic fibrosis (CF), and the CFTR-W1282X mutation results in severe CF. Current therapies for CF benefit most patients, but targeted therapy for patients with the W1282X mutation is lacking. This study explores a potential solution by using an exon-skipping antisense oligonucleotide strategy to bypass nonsense-mediated mRNA decay (NMD) and increase the expression of CFTR protein. The results pave the way for developing allele-specific therapy for CF caused by the W1282X mutation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(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
Medicine, Research & Experimental
Melita Kaltak, Rocio Blanco-Garavito, Laurie L. Molday, Claire-Marie Dhaenens, Eric E. Souied, Gerard Platenburg, Jim Swildens, Robert S. Molday, Frans P. M. Cremers
Summary: This study investigated the exon skipping phenomenon of exon 17 in the ABCA4 gene associated with Stargardt disease (STGD1) and designed corresponding oligonucleotides to induce exon 17 skipping. The results showed that the deletion of exon 17 in ABCA4 does not result in the absence of protein activity and does not cause a severe STGD1 phenotype when in trans with a null allele. Therefore, the impact of severe variants in exon 17 can potentially be ameliorated by exon skipping using antisense oligonucleotides (AONs), generating partial ABCA4 activity in STGD1 patients.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Review
Genetics & Heredity
Gokce Eser, Haluk Topaloglu
Summary: Molecular treatments for Duchenne muscular dystrophy, such as exon skipping, have been in clinical practice for over 15 years. Promising clinical trials based on earlier works have shown potential in initiating dystrophin production to slow down disease progression. Some of these treatments have received conditional approval from health authorities, but further data accumulation is still necessary.
Article
Biochemistry & Molecular Biology
Elena Marchesi, Matteo Bovolenta, Lorenzo Preti, Massimo L. Capobianco, Kamel Mamchaoui, Monica Bertoldo, Daniela Perrone
Summary: The study found that ASO oligonucleotides conjugated with ursodeoxycholic acid (UDCA) showed better performance in targeting human DMD exon 51 compared to unconjugated ones, with an average 9.5-fold increase in exon skipping efficiency.
Article
Biochemistry & Molecular Biology
Kentaro Ito, Hideo Takakusa, Masayo Kakuta, Akira Kanda, Nana Takagi, Hiroyuki Nagase, Nobuaki Watanabe, Daigo Asano, Ryoya Goda, Takeshi Masuda, Akifumi Nakamura, Yoshiyuki Onishi, Toshio Onoda, Makoto Koizumi, Yasuhiro Takeshima, Masafumi Matsuo, Kiyosumi Takaishi
Summary: Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by gene mutations, and the exon-skipping therapy using modified antisense oligonucleotides (AOs) shows promising preclinical characteristics for potential clinical application to improve muscle symptoms and cardiac dysfunction in DMD patients.
CURRENT ISSUES IN MOLECULAR BIOLOGY
(2021)
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
Biochemistry & Molecular Biology
Chiara Pacelli, Alice Rossi, Michele Milella, Teresa Colombo, Loredana Le Pera
Summary: Precision medicine in oncology has made significant progress, but many cancer driver genes are still difficult to target with drugs. RNA-based methods, such as antisense oligonucleotides (ASOs), can induce targeted exon skipping (ES) and provide a promising alternative. This work presents a comprehensive computational procedure for developing ES-based cancer treatments, including target-exon selection, in silico prediction of ES products, and identification of optimal ASOs for experimental validation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
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
Biochemistry & Molecular Biology
Alejandro Gimenez Molina, Prithi Raguraman, Line Delcomyn, Rakesh N. Veedu, Poul Nielsen
Summary: This study presents a nucleotide monomer with a 1-phenyl-1,2,3-triazole group attached to the 5-position of 2'-O-methyluridine, along with a derivative further substituted with a p-sulfonamide group on the phenyl ring. Both compounds were easily synthesized and showed synergistic effects when introduced into oligonucleotides and hybridized with complementary RNA. The combination of stacking of the phenyltriazoles and conformational steering from the 2'-OMe group resulted in thermally stable duplexes. Exon skipping in the dystrophin transcript was efficiently achieved using 20-mer 2'-OMePS sequences with phenyltriazoles introduced in different positions with and without the sulfonamide substitution, comparable to the effect of the 2'-OMePS reference ASO.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
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
Biochemistry & Molecular Biology
Jessica M. Cale, Kane Greer, Sue Fletcher, Steve D. Wilton
Summary: Marfan syndrome is a dominantly inherited connective tissue disorder caused by mutations in the FBN1 gene. In vitro experiments have shown that exclusion of exon 52 using antisense oligonucleotides has the potential to treat the disease by restoring monomer homology. More research is needed to explore the impact of exon skipping on fibrillin-1 function and its therapeutic implications.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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)
