Developing DMD therapeutics: a review of the effectiveness of small molecules, stop-codon readthrough, dystrophin gene replacement, and exon-skipping therapies

Sheikh, Omar

doi:10.1080/13543784.2021.1868434

Cited by 47 publications

(36 citation statements)

References 115 publications

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“…Nonsense mutations are the major cause of cystic fibrosis (CF) or Duchenne’s muscular dystrophy (DMD) [ 12 ]; both genes have been targeted for PTC-readthrough therapies to restore functional protein expression and reduce disease symptoms, but pre-clinical trials have shown limited success [ 13 , 14 ]. Chemically stimulated readthrough of in-frame PTCs present in mRNA enables suppression of the PTC by promoting interaction with near-cognate transfer RNAs (nc-tRNAs) and incorporation of an amino acid into the nascent protein chain [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Properties of Non-Aminoglycoside Compounds Used to Stimulate Translational Readthrough of PTC Mutations in Primary Ciliary Dyskinesia

Dąbrowski

Bukowy-Bieryłło

Jackson

et al. 2021

IJMS

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Primary ciliary dyskinesia (PCD) is a rare disease with autosomal recessive inheritance, caused mostly by bi-allelic gene mutations that impair motile cilia structure and function. Currently, there are no causal treatments for PCD. In many disease models, translational readthrough of premature termination codons (PTC-readthrough) induced by aminoglycosides has been proposed as an effective way of restoring functional protein expression and reducing disease symptoms. However, variable outcomes of pre-clinical trials and toxicity associated with long-term use of aminoglycosides prompt the search for other compounds that might overcome these problems. Because a high proportion of PCD-causing variants are nonsense mutations, readthrough therapies are an attractive option. We tested a group of chemical compounds with known PTC-readthrough potential (ataluren, azithromycin, tylosin, amlexanox, and the experimental compound TC007), collectively referred to as non-aminoglycosides (NAGs). We investigated their PTC-readthrough efficiency in six PTC mutations found in Polish PCD patients, in the context of cell and cilia health, and in comparison to the previously tested aminoglycosides. The NAGs did not compromise the viability of the primary nasal respiratory epithelial cells, and the ciliary beat frequency was retained, similar to what was observed for gentamicin. In HEK293 cells transfected with six PTC-containing inserts, the tested compounds stimulated PTC-readthrough but with lower efficiency than aminoglycosides. The study allowed us to select compounds with minimal negative impact on cell viability and function but still the potential to induce PTC-readthrough.

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Section: Introductionmentioning

confidence: 99%

Properties of Non-Aminoglycoside Compounds Used to Stimulate Translational Readthrough of PTC Mutations in Primary Ciliary Dyskinesia

Dąbrowski

Bukowy-Bieryłło

Jackson

et al. 2021

IJMS

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“…For example, antisense oligonucleotide-mediated exon skipping targets pre-mRNA splicing to restore shortened but functional proteins [48], while the CRISPR/Cas9 system is used to edit the defective DMD gene [49]. Currently, four exon skipping antisense oligonucleotides are FDA-approved for use in the treatment of DMD patients: Amondys 45 (casimersen), Viltepso (viltolarsen), Exondys 51 (eteplirsen) and Vyondys 53 (golodirsen) [50][51][52]. Moreover, CRISPR/ Cas9-based strategies have provided promising therapeutic approaches; however, limitations remain, including the risk of off-target gene editing, and further research is required [50].…”

Section: Molecular Background Of Duchenne Muscular Dystrophymentioning

confidence: 99%

Therapeutic aspects of cell signaling and communication in Duchenne muscular dystrophy

Starosta

Konieczny

2021

Cell. Mol. Life Sci.

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Duchenne muscular dystrophy (DMD) is a devastating chromosome X-linked disease that manifests predominantly in progressive skeletal muscle wasting and dysfunctions in the heart and diaphragm. Approximately 1/5000 boys and 1/50,000,000 girls suffer from DMD, and to date, the disease is incurable and leads to premature death. This phenotypic severity is due to mutations in the DMD gene, which result in the absence of functional dystrophin protein. Initially, dystrophin was thought to be a force transducer; however, it is now considered an essential component of the dystrophin-associated protein complex (DAPC), viewed as a multicomponent mechanical scaffold and a signal transduction hub. Modulating signal pathway activation or gene expression through epigenetic modifications has emerged at the forefront of therapeutic approaches as either an adjunct or stand-alone strategy. In this review, we propose a broader perspective by considering DMD to be a disease that affects myofibers and muscle stem (satellite) cells, as well as a disorder in which abrogated communication between different cell types occurs. We believe that by taking this systemic view, we can achieve safe and holistic treatments that can restore correct signal transmission and gene expression in diseased DMD tissues.

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“…For example, Sarepta (Cambridge, MA, USA) works intensively with RNA-targeted therapeutic candidates for different types of RNA, using phosphorodiamidate morpholino oligomers (PMOs) as antisense ONs, attached to CPPs (PPMO) such as (R-Ahx-R) 4 , (6-aminohexanoic acid-spaced oligo-arginine). The development of next-generation PMO-based chemistries for advanced RNA-targeted therapeutics with enhanced tissue targeting, intracellular delivery, target selectivity and drug potency is in progress [ 53 ].…”

Section: Transportanmentioning

confidence: 99%

Cell-Penetrating Peptides and Transportan

Langel

2021

Pharmaceutics

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In the most recent 25–30 years, multiple novel mechanisms and applications of cell-penetrating peptides (CPP) have been demonstrated, leading to novel drug delivery systems. In this review, I present a brief introduction to the CPP area with selected recent achievements. This is followed by a nostalgic journey into the research in my own laboratories, which lead to multiple CPPs, starting from transportan and paving a way to CPP-based therapeutic developments in the delivery of bio-functional materials, such as peptides, proteins, vaccines, oligonucleotides and small molecules, etc.

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Developing DMD therapeutics: a review of the effectiveness of small molecules, stop-codon readthrough, dystrophin gene replacement, and exon-skipping therapies

Cited by 47 publications

References 115 publications

Properties of Non-Aminoglycoside Compounds Used to Stimulate Translational Readthrough of PTC Mutations in Primary Ciliary Dyskinesia

Properties of Non-Aminoglycoside Compounds Used to Stimulate Translational Readthrough of PTC Mutations in Primary Ciliary Dyskinesia

Therapeutic aspects of cell signaling and communication in Duchenne muscular dystrophy

Cell-Penetrating Peptides and Transportan

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