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Open accessJournal ArticleDOI: 10.1080/14712598.2021.1832462

Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy

04 Mar 2021-Expert Opinion on Biological Therapy (Taylor & Francis)-Vol. 21, Iss: 3, pp 343-359
Abstract: Exon skipping compounds restoring the dystrophin transcript reading frame have received regulatory approval for Duchenne muscular dystrophy (DMD). Recently, focus shifted to developing compounds to...

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Topics: Exon skipping (72%), Duchenne muscular dystrophy (66%), Dystrophin (52%)
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Open accessJournal Article
18 Apr 2017-Neurology
Abstract: Objective: Phosphorodiamidate morpholino oligomers (PMOs) are synthetic nucleic acid analogs that can be designed to sequence-specifically block spliceosomes from binding to dystrophin pre-mRNA, resulting in omission of the targeted exon from the transcript and restoration of the reading frame with the goal of enabling synthesis of internally-shortened dystrophin. Background: DMD, a rare, X-linked genetic disease results in progressive muscle degeneration and premature death. DMD is primarily caused by whole exon deletions in the dystrophin gene resulting in a shift of the mRNA reading frame that prevents production of functional dystrophin protein. Design/Methods: As of June 3, 2016, 81 of 150 treated patients had received weekly eteplirsen for ≥1 year. Results: PMO eteplirsen received accelerated approval in the US for patients with a dystrophin gene mutation amenable to exon 51 skipping based on an increase in dystrophin in skeletal muscle in some patients. Mean dystrophin increases as measured by Western blot were observed following 180 weeks of treatment in the pivotal Phase II Studies 201/202 when compared to untreated DMD controls (N=11; +0.85%, p=0.007) and at Week 48 in Phase III Study PROMOVI when compared to baseline (N=12; +0.28%, p=0.008). Immunohistochemistry analysis at Week 180 in Study 201/202 also showed mean increases in dystrophin as measured by % dystrophin-positive fibers (N=11; +16.27%, p 4.5 years of treatment. Conclusions: Eteplirsen is the first exon skipping therapy approved for the treatment of Duchenne muscular dystrophy amenable to exon 51 skipping. Lessons learned from the eteplirsen clinical development program can aid in development of PMO therapies targeting additional exons. Study Supported by: Sarepta Therapeutics, Inc. Disclosure: Dr. Charleston has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Schnell has received personal compensation for activities with Sarepta Therapeutics as a full time employee. Dr. Dworzak has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Donoghue has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Lynch has received personal compensation for activities with Sarepta Therapeutics, Inc. as an employee. Dr. Lewis has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Rodino-Klapac has nothing to disclose. Dr. Sahenk has nothing to disclose. Dr. Voss has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. DeAlwis has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Frank has received personal compensation for activities with Sarepta Therapeutics, Inc. as an employee. Dr. Eliopoulos has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Mendell has received personal compensation for activities with Sarepta Therapeutics, Inc.

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Topics: Eteplirsen (71%), Duchenne muscular dystrophy (59%), Exon skipping (52%)

335 Citations


Open accessJournal ArticleDOI: 10.3390/JCM10040820
Abstract: Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy affecting ~1:5000 live male births. Following the identification of pathogenic variations in the dystrophin gene in 1986, the underlining genotype/phenotype correlations emerged and the role of the dystrophin protein was elucidated in skeletal, smooth, and cardiac muscles, as well as in the brain. When the dystrophin protein is absent or quantitatively or qualitatively modified, the muscle cannot sustain the stress of repeated contractions. Dystrophin acts as a bridging and anchoring protein between the sarcomere and the sarcolemma, and its absence or reduction leads to severe muscle damage that eventually cannot be repaired, with its ultimate substitution by connective tissue and fat. The advances of an understanding of the molecular pathways affected in DMD have led to the development of many therapeutic strategies that tackle different aspects of disease etiopathogenesis, which have recently led to the first successful approved orphan drugs for this condition. The therapeutic advances in this field have progressed exponentially, with second-generation drugs now entering in clinical trials as gene therapy, potentially providing a further effective approach to the condition.

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Topics: Duchenne muscular dystrophy (71%), Dystrophin (63%), Muscular dystrophy (62%) ... read more

10 Citations


Open accessJournal ArticleDOI: 10.3389/FCELL.2021.662837
Abstract: The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) represents a major advance for the development of human disease models. The emerging of this technique fostered the concept of "disease in a dish," which consists into the generation of patient-specific models in vitro. Currently, iPSCs are used to study pathological molecular mechanisms caused by genetic mutations and they are considered a reliable model for high-throughput drug screenings. Importantly, precision-medicine approaches to treat monogenic disorders exploit iPSCs potential for the selection and validation of lead candidates. For example, antisense oligonucleotides (ASOs) were tested with promising results in myoblasts or motor neurons differentiated from iPSCs of patients affected by either Duchenne muscular dystrophy or Amyotrophic lateral sclerosis. However, the use of iPSCs needs additional optimization to ensure translational success of the innovative strategies based on gene delivery through adeno associated viral vectors (AAV) for these diseases. Indeed, to establish an efficient transduction of iPSCs with AAV, several aspects should be optimized, including viral vector serotype, viral concentration and timing of transduction. This review will outline the use of iPSCs as a model for the development and testing of gene therapies for neuromuscular and motor neuron disorders. It will then discuss the advantages for the use of this versatile tool for gene therapy, along with the challenges associated with the viral vector transduction of iPSCs.

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2 Citations


Open accessJournal ArticleDOI: 10.1126/SCIADV.ABI8787
Amaia Paredes‐Redondo1, Peter Harley2, Eleni Maniati1, David Ryan3  +13 moreInstitutions (7)
10 Sep 2021-Science Advances
Abstract: Duchenne muscular dystrophy (DMD) is caused by dystrophin gene mutations leading to skeletal muscle weakness and wasting. Dystrophin is enriched at the neuromuscular junction (NMJ), but how NMJ abn...

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1 Citations


Open accessBook ChapterDOI: 10.5772/INTECHOPEN.96738
13 Mar 2021-
Abstract: Duchenne muscular dystrophy is a complex and severe orphan disease. It develops when the organism lacks the expression of dystrophin - a large structural protein. Dystrophin is transcribed from the largest gene in the human genome. At the moment, there is no cure available. Dozens of groups all over the world search for cure. Animal models are an important component of both the fundamental research and therapy development. Many animal models reproducing the features of disease were created and actively used since the late 80’s until present. The species diversity spans from invertebrates to primates and the genetic diversity of these models spans from single mutations to full gene deletions. The models are often non-interchangeable; while one model may be used for particular drug design it may be useless for another. Here we describe existing models, discuss their advantages and disadvantages and potential applications for research and therapy development.

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1 Citations


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132 results found


Journal ArticleDOI: 10.1016/0092-8674(87)90579-4
24 Dec 1987-Cell
Abstract: The protein product of the human Duchenne muscular dystrophy locus (DMD) and its mouse homolog (mDMD) have been identified by using polyclonal antibodies directed against fusion proteins containing two distinct regions of the mDMD cDNA. The DMD protein is shown to be approximately 400 kd and to represent approximately 0.002% of total striated muscle protein. This protein is also detected in smooth muscle (stomach). Muscle tissue isolated from both DMD-affected boys and mdx mice contained no detectable DMD protein, suggesting that these genetic disorders are homologous. Since mdx mice present no obvious clinical abnormalities, the identification of the mdx mouse as an animal model for DMD has important implications with regard to the etiology of the lethal DMD phenotype. We have named the protein dystrophin because of its identification via the isolation of the Duchenne muscular dystrophy locus.

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Topics: mdx mouse (72%), Duchenne muscular dystrophy (67%), Becker's muscular dystrophy (66%) ... read more

4,123 Citations


Open accessJournal ArticleDOI: 10.1016/J.TIBTECH.2013.04.004
Abstract: Zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) comprise a powerful class of tools that are redefining the boundaries of biological research. These chimeric nucleases are composed of programmable, sequence-specific DNA-binding modules linked to a nonspecific DNA cleavage domain. ZFNs and TALENs enable a broad range of genetic modifications by inducing DNA double-strand breaks that stimulate error-prone nonhomologous end joining or homology-directed repair at specific genomic locations. Here, we review achievements made possible by site-specific nuclease technologies and discuss applications of these reagents for genetic analysis and manipulation. In addition, we highlight the therapeutic potential of ZFNs and TALENs and discuss future prospects for the field, including the emergence of clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas-based RNA-guided DNA endonucleases.

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Topics: Genome editing (65%), Transcription activator-like effector nuclease (64%), CRISPR (59%) ... read more

2,801 Citations


Journal ArticleDOI: 10.1016/0092-8674(88)90383-2
M. Koenig1, M. Koenig2, Anthony P. Monaco2, Anthony P. Monaco1  +3 moreInstitutions (3)
22 Apr 1988-Cell
Abstract: The complete sequence of the human Duchenne muscular dystrophy (DMD) cDNA has been determined. The 3685 encoded amino acids of the protein product, dystrophin, can be separated into four domains. The 240 amino acid N-terminal domain has been shown to be conserved with the actin-binding domain of alpha-actinin. A large second domain is predicted to be rod-shaped and formed by the succession of 25 triple-helical segments similar to the repeat domains of spectrin. The repeat segment is followed by a cysteine-rich segment that is similar in part to the entire COOH domain of the Dictyostelium alpha-actinin, while the 420 amino acid C-terminal domain of dystrophin does not show any similarity to previously reported proteins. The functional significance of some of the domains is addressed relative to the phenotypic characteristics of some Becker muscular dystrophy patients. Dystrophin shares many features with the cytoskeletal protein spectrin and alpha-actinin and is a large structural protein that is likely to adopt a rod shape about 150 nm in length.

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1,479 Citations


Journal ArticleDOI: 10.1016/0888-7543(88)90113-9
01 Jan 1988-Genomics
Abstract: Deletions giving rise to Duchenne muscular dystrophy (DMD) and the less severe Becker muscular dystrophy (BMD) occur in the same large gene on the short arm of the human X chromosome. We present a molecular mechanism to explain the clinical difference in severity between DMD and BMD patients who bear partial deletions of the same gene locus. The model is based on the breakpoints of intragenic deletions and their effect on the translation of triplet codons into amino acids of the protein product. Deletions identified in three DMD patients are shown to shift the translational open reading frame (ORF) of triplet codons for amino acids, and each deletion is predicted to result in a truncated, abnormal protein product. Deletions identified in three BMD patients are shown to maintain the translational ORF for amino acids and predict a shorter, lower molecular weight protein. The smaller protein product is presumed to be semifunctional and to result in a milder clinical phenotype. The same ORF mechanism is also applicable to potential 5' and 3' intron splice mutations and their effect on protein production and clinical phenotype.

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Topics: Open reading frame (54%), Duchenne muscular dystrophy (52%), Locus (genetics) (51%) ... read more

1,080 Citations


Open accessJournal ArticleDOI: 10.1016/S0140-6736(11)60756-3
13 Aug 2011-The Lancet
Abstract: Summary Background We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. Method We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5–15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. Findings 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9% (95% CI 7·1–10·6) to 16·4% (10·8–22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0·9% to 17%, and from 0% to 7·7% of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. Interpretation The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. Funding UK Medical Research Council; AVI BioPharma.

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Topics: Duchenne muscular dystrophy (68%), Drisapersen (63%), Exon skipping (60%) ... read more

786 Citations


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