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  1. Article ; Online: The Future of Exon Skipping for Duchenne Muscular Dystrophy.

    Aartsma-Rus, Annemieke

    Human gene therapy

    2023  Volume 34, Issue 9-10, Page(s) 372–378

    Abstract: Antisense oligonucleotide (ASO)-mediated exon skipping can restore the open reading frame of dystrophin transcripts for Duchenne muscular dystrophy (DMD) patients. This allows production of internally deleted dystrophin proteins as found in the later ... ...

    Abstract Antisense oligonucleotide (ASO)-mediated exon skipping can restore the open reading frame of dystrophin transcripts for Duchenne muscular dystrophy (DMD) patients. This allows production of internally deleted dystrophin proteins as found in the later onset, less severely progressive Becker muscular dystrophy. At present, ASOs that induce exon skipping and dystrophin restoration are approved for the treatment of DMD by the regulatory agencies of the United States and Japan. However, approval was based on restoration of very small amounts of dystrophin and the approved ASOs apply to only a subset of patients. This expert perspective evaluates ways to improve ASO efficiency that are currently in or close to clinical trials, as well as ways to improve applicability of this mutation-specific approach.
    MeSH term(s) Humans ; Muscular Dystrophy, Duchenne/genetics ; Dystrophin/genetics ; Oligonucleotides, Antisense/therapeutic use ; Mutation ; Exons
    Chemical Substances Dystrophin ; Oligonucleotides, Antisense
    Language English
    Publishing date 2023-05-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1028152-6
    ISSN 1557-7422 ; 1043-0342
    ISSN (online) 1557-7422
    ISSN 1043-0342
    DOI 10.1089/hum.2023.026
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2988: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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  2. Book: Exon skipping

    Aartsma-Rus, Annemieke

    methods and protocols

    (Methods in molecular biology ; 867 ; Springer protocols)

    2012  

    Author's details ed. by Annemieke Aartsma-Rus
    Series title Methods in molecular biology ; 867
    Springer protocols
    Collection
    Language English
    Size XI, 440 S. : Ill., graph. Darst.
    Publisher Humana Press
    Publishing place New York u.a.
    Publishing country United States
    Document type Book
    HBZ-ID HT017209985
    ISBN 978-1-61779-766-8 ; 9781617797675 ; 1-61779-766-9 ; 1617797677
    Database Catalogue ZB MED Medicine, Health

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    Shelf markLoan statusLocation
    2012 A 1802 order for loan Magazin

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  3. Article: Good news for the

    Aartsma-Rus, Annemieke

    Molecular therapy. Nucleic acids

    2022  Volume 30, Page(s) 355–356

    Language English
    Publishing date 2022-11-08
    Publishing country United States
    Document type News
    ZDB-ID 2662631-7
    ISSN 2162-2531
    ISSN 2162-2531
    DOI 10.1016/j.omtn.2022.10.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Next steps for the optimization of exon therapy for Duchenne muscular dystrophy.

    Filonova, Galina / Aartsma-Rus, Annemieke

    Expert opinion on biological therapy

    2023  Volume 23, Issue 2, Page(s) 133–143

    Abstract: Introduction: It is established that the exon-skipping approach can restore dystrophin in Duchenne muscular dystrophy (DMD) patients. However, dystrophin restoration levels are low, and the field is evolving to provide solutions for improved exon ... ...

    Abstract Introduction: It is established that the exon-skipping approach can restore dystrophin in Duchenne muscular dystrophy (DMD) patients. However, dystrophin restoration levels are low, and the field is evolving to provide solutions for improved exon skipping. DMD is a neuromuscular disorder associated with chronic muscle tissue loss attributed to the lack of dystrophin, which causes muscle inflammation, fibrosis formation, and impaired regeneration. Currently, four antisense oligonucleotides (AONs) based on phosphorodiamidate morpholino oligomer (PMO) chemistry are approved by US Food and Drug Administration for exon skipping therapy of eligible DMD patients.
    Areas covered: This review describes a preclinical and clinical experience with approved and newly developed AONs for DMD, outlines efforts that have been done to enhance AON efficiency, reviews challenges of clinical trials, and summarizes the current state of the exon skipping approach in the DMD field.
    Expert opinion: The exon skipping approach for DMD is under development, and several chemical modifications with improved properties are under (pre)-clinical investigation. Despite existing advantages of these modifications, their safety and effectiveness have to be examined in clinical trials, which are planned or ongoing. Furthermore, we propose clinical settings using natural history controls to facilitate studying the functional effect of the therapy.
    MeSH term(s) United States ; Humans ; Muscular Dystrophy, Duchenne/genetics ; Muscular Dystrophy, Duchenne/therapy ; Dystrophin/genetics ; Genetic Therapy ; Oligonucleotides, Antisense/therapeutic use ; Exons
    Chemical Substances Dystrophin ; Oligonucleotides, Antisense
    Language English
    Publishing date 2023-01-21
    Publishing country England
    Document type Review ; Journal Article
    ZDB-ID 2052501-1
    ISSN 1744-7682 ; 1471-2598
    ISSN (online) 1744-7682
    ISSN 1471-2598
    DOI 10.1080/14712598.2023.2169070
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6094: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Antisense Oligonucleotide-Mediated Downregulation of IGFBPs Enhances IGF-1 Signaling.

    Yavas, Alper / van Putten, Maaike / Aartsma-Rus, Annemieke

    Journal of neuromuscular diseases

    2024  Volume 11, Issue 2, Page(s) 299–314

    Abstract: Insulin-like growth factor-1 (IGF-1) has been considered as a therapeutic agent for muscle wasting conditions including Duchenne muscular dystrophy as it stimulates muscle regeneration, growth and function. Several preclinical and clinical studies have ... ...

    Abstract Insulin-like growth factor-1 (IGF-1) has been considered as a therapeutic agent for muscle wasting conditions including Duchenne muscular dystrophy as it stimulates muscle regeneration, growth and function. Several preclinical and clinical studies have been conducted to show the therapeutic potential of IGF-1, however, delivery issues, short half-life and isoform complexity have impose challenges. Antisense oligonucleotides (AONs) are able to downregulate target proteins by interfering with their transcripts. Here, we investigated the feasibility of enhancing IGF-1 signaling by downregulation of IGF-binding proteins. We observed that out of frame exon skipping of Igfbp1 and Igfbp3 downregulated their protein expression, which increased Akt phosphorylation on the downstream IGF-1 signaling in vitro. 3'RNA sequencing analysis revealed the related transcriptome in C2C12 cells in response to IGFBP3 downregulation. The AONs did however not induce any exon skipping or protein knockdown in mdx mice after 6 weeks of systemic treatment. We conclude that IGFBP downregulation could be a good strategy to increase IGF-1 signaling but alternative tools are needed for efficient delivery and knockdown in vivo.
    MeSH term(s) Mice ; Animals ; Oligonucleotides, Antisense/pharmacology ; Oligonucleotides, Antisense/therapeutic use ; Dystrophin/genetics ; Mice, Inbred mdx ; Insulin-Like Growth Factor I/metabolism ; Down-Regulation ; Oligonucleotides ; Insulin-Like Growth Factor Binding Proteins/genetics ; Insulin-Like Growth Factor Binding Proteins/metabolism
    Chemical Substances Oligonucleotides, Antisense ; Dystrophin ; Insulin-Like Growth Factor I (67763-96-6) ; Oligonucleotides ; Insulin-Like Growth Factor Binding Proteins
    Language English
    Publishing date 2024-01-08
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2214-3602
    ISSN (online) 2214-3602
    DOI 10.3233/JND-230118
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Applying Lessons Learned from Developing Exon Skipping for Duchenne to Developing Individualized Exon Skipping Therapy for Patients with Neurodegenerative Diseases

    Aartsma-Rus, Annemieke

    Synlett

    2023  

    Abstract: Antisense oligonucleotides (ASOs) are short, modified pieces of DNA that are chemically modified. They can be used to induce exon skipping and treat Duchenne muscular dystrophy (DMD) patients by interfering with the splicing process so mutated dystrophin ...

    Abstract Antisense oligonucleotides (ASOs) are short, modified pieces of DNA that are chemically modified. They can be used to induce exon skipping and treat Duchenne muscular dystrophy (DMD) patients by interfering with the splicing process so mutated dystrophin transcripts become readable allowing production of partially functional dystrophin proteins, rather than nonfunctional dystrophins. After over 2 decades of research, 4 ASOs are FDA approved for DMD, but clinical effects are suboptimal due to limited delivery to skeletal muscle. At the same time, ASOs for brain diseases result in much more functional impact, because local delivery allows higher exposure to the target tissue at a low dose and infrequent treatment regimen. This has opened the way to develop ASOs in an individualized setting, as was exemplified by the development of Milasen to treat a patient with CLN7 Batten disease. In this perspective paper I will share my personal journey as one of the pioneers of ASO-mediated exon skipping development for DMD, currently applying expertise gained and lessons learned along the way to develop exon skipping ASOs for eligible patients with genetic brain diseases in a national and international setting. 1

    Duchenne and Antisense-Mediated Exon Skipping 2

    Opportunities for Treating Central Nervous System Diseases and Developing Individualized ASOs for Central Nervous System Diseases 3

    Collaborative Spirit to Develop Individualized Treatments Globally 4

    Global Implementation 5

    Concluding Remarks
    Keywords antisense oligonucleotide ; exon skipping ; N-of-1 treatment ; rare disease ; therapy
    Language English
    Publishing date 2023-11-15
    Publisher Georg Thieme Verlag KG
    Publishing place Stuttgart ; New York
    Document type Article
    ZDB-ID 2042012-2
    ISSN 1437-2096 ; 0936-5214
    ISSN (online) 1437-2096
    ISSN 0936-5214
    DOI 10.1055/a-2211-6490
    Database Thieme publisher's database

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  7. Article ; Online: In Vitro Delivery of PMOs in Myoblasts by Electroporation.

    Goossens, Remko / Aartsma-Rus, Annemieke

    Methods in molecular biology (Clifton, N.J.)

    2022  Volume 2434, Page(s) 191–205

    Abstract: Antisense oligonucleotides (AONs) are small synthetic molecules of therapeutic interest for a variety of human disease. Their ability to bind mRNA and affect its splicing gives AONs potential use for exon skipping therapies aimed at restoring the ... ...

    Abstract Antisense oligonucleotides (AONs) are small synthetic molecules of therapeutic interest for a variety of human disease. Their ability to bind mRNA and affect its splicing gives AONs potential use for exon skipping therapies aimed at restoring the dystrophin transcript reading frame for Duchenne muscular dystrophy (DMD) patients. The neutrally charged phosphorodiamidate morpholino oligomers (PMOs) are a stable and relatively nontoxic AON modification. To assess exon skipping efficiency in vitro, it is important to deliver them to target cells. Here, we describe a method for the delivery of PMOs to myoblasts by electroporation. The described protocol for the Amaxa 4D X unit nucleofector system allows efficient processing of 16 samples in one nucleocuvette strip, aiding in high-throughput PMO efficacy screens.
    MeSH term(s) Dystrophin/genetics ; Dystrophin/metabolism ; Electroporation ; Genetic Therapy/methods ; Humans ; Morpholinos/genetics ; Morpholinos/therapeutic use ; Muscular Dystrophy, Duchenne/drug therapy ; Muscular Dystrophy, Duchenne/therapy ; Myoblasts/metabolism
    Chemical Substances Dystrophin ; Morpholinos
    Language English
    Publishing date 2022-02-25
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-2010-6_12
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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  8. Article ; Online: Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders.

    Lauffer, Marlen C / van Roon-Mom, Willeke / Aartsma-Rus, Annemieke

    Communications medicine

    2024  Volume 4, Issue 1, Page(s) 6

    Abstract: Antisense oligonucleotides (ASOs) are incredibly versatile molecules that can be designed to specifically target and modify RNA transcripts to slow down or halt rare genetic disease progression. They offer the potential to target groups of patients or ... ...

    Abstract Antisense oligonucleotides (ASOs) are incredibly versatile molecules that can be designed to specifically target and modify RNA transcripts to slow down or halt rare genetic disease progression. They offer the potential to target groups of patients or can be tailored for individual cases. Nonetheless, not all genetic variants and disorders are amenable to ASO-based treatments, and hence, it is important to consider several factors before embarking on the drug development journey. Here, we discuss which genetic disorders have the potential to benefit from a specific type of ASO approach, based on the pathophysiology of the disease and pathogenic variant type, as well as those disorders that might not be suitable for ASO therapies. We further explore additional aspects, such as the target tissues, intervention time points, and potential clinical benefits, which need to be considered before developing a compound. Overall, we provide an overview of the current potentials and limitations of ASO-based therapeutics for the treatment of monogenic disorders.
    Language English
    Publishing date 2024-01-05
    Publishing country England
    Document type Journal Article ; Review
    ISSN 2730-664X
    ISSN (online) 2730-664X
    DOI 10.1038/s43856-023-00419-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: 'N of 1' therapies need a better model.

    Aartsma-Rus, Annemieke

    Nature medicine

    2020  Volume 27, Issue 6, Page(s) 939

    MeSH term(s) Genetic Diseases, Inborn/epidemiology ; Genetic Diseases, Inborn/genetics ; Genetic Diseases, Inborn/therapy ; Humans ; Oligonucleotides, Antisense/therapeutic use
    Chemical Substances Oligonucleotides, Antisense
    Language English
    Publishing date 2020-05-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-021-01380-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4212: Show issues Location:
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  10. Article ; Online: From Failure to Meet the Clinical Endpoint to U.S. Food and Drug Administration Approval: 15th Antisense Oligonucleotide Therapy Approved Qalsody (Tofersen) for Treatment of

    van Roon-Mom, Willeke / Ferguson, Chantal / Aartsma-Rus, Annemieke

    Nucleic acid therapeutics

    2023  Volume 33, Issue 4, Page(s) 234–237

    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis/drug therapy ; Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Oligonucleotides, Antisense/therapeutic use ; Superoxide Dismutase-1/genetics ; United States ; United States Food and Drug Administration ; Drug Approval ; Endpoint Determination
    Chemical Substances Oligonucleotides, Antisense ; SOD1 protein, human ; Superoxide Dismutase-1 (EC 1.15.1.1) ; tofersen (2NU6F9601K)
    Language English
    Publishing date 2023-08-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2639888-6
    ISSN 2159-3345 ; 2159-3337
    ISSN (online) 2159-3345
    ISSN 2159-3337
    DOI 10.1089/nat.2023.0027
    Database MEDical Literature Analysis and Retrieval System OnLINE

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