Pharmacology and toxicology of eteplirsen and SRP-5051 for DMD exon 51 skipping: an update

Sheikh, Omar; Yokota, Toshifumi

doi:10.1007/s00204-021-03184-z

Cited by 32 publications

(23 citation statements)

References 87 publications

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“…The first-in-class fascin inhibitor NP-G2-044 recently passed a phase Ia clinical trial to evaluate safety and anti-tumor activity in patients with advanced and metastatic solid tumors (https://clinicaltrials.gov/ct2/show/NCT031 99586, accessed on 9 February 2022). Golodirsen, antisense oligonucleotide Vyondys 53, and related oligonucleotides are unique drugs that target the dystrophin gene to treat Duchenne muscular dystrophy (DMD) [123][124][125]. The binding of the oligonucleotide to DNA alters splicing to generate a functional gene product.…”

Section: Actin and Abp As A Drug Targetmentioning

confidence: 99%

Actin-Associated Proteins and Small Molecules Targeting the Actin Cytoskeleton

Gao,

Nakamura

2022

IJMS

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Actin-associated proteins (AAPs) act on monomeric globular actin (G-actin) and polymerized filamentous actin (F-actin) to regulate their dynamics and architectures which ultimately control cell movement, shape change, division; organelle localization and trafficking. Actin-binding proteins (ABPs) are a subset of AAPs. Since actin was discovered as a myosin-activating protein (hence named actin) in 1942, the protein has also been found to be expressed in non-muscle cells, and numerous AAPs continue to be discovered. This review article lists all of the AAPs discovered so far while also allowing readers to sort the list based on the names, sizes, functions, related human diseases, and the dates of discovery. The list also contains links to the UniProt and Protein Atlas databases for accessing further, related details such as protein structures, associated proteins, subcellular localization, the expression levels in cells and tissues, mutations, and pathology. Because the actin cytoskeleton is involved in many pathological processes such as tumorigenesis, invasion, and developmental diseases, small molecules that target actin and AAPs which hold potential to treat these diseases are also listed.

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Section: Actin and Abp As A Drug Targetmentioning

confidence: 99%

Actin-Associated Proteins and Small Molecules Targeting the Actin Cytoskeleton

Gao,

Nakamura

2022

IJMS

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“…Results at 12 weeks showed that SRP-5051 dosed monthly at 30 mg/kg increased mean dystrophin expression to 6.55%, consistently higher than the other dosing cohorts and weekly eteplirsen at 24 weeks (Sarepta, 2021b). Despite added therapeutic effectiveness, safety and tolerability concerns need to be further investigated, as there were 3 serious, treatmentemergent AEs in two patients in the 30 mg/kg cohort, including two cases of hypomagnesemia (Sarepta, 2021b;Sheikh and Yokota, 2022).…”

Section: Srp-5051 (Vesleteplirsen)mentioning

confidence: 99%

Drug development progress in duchenne muscular dystrophy

et al. 2022

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Duchenne muscular dystrophy (DMD) is a severe, progressive, and incurable X-linked disorder caused by mutations in the dystrophin gene. Patients with DMD have an absence of functional dystrophin protein, which results in chronic damage of muscle fibers during contraction, thus leading to deterioration of muscle quality and loss of muscle mass over time. Although there is currently no cure for DMD, improvements in treatment care and management could delay disease progression and improve quality of life, thereby prolonging life expectancy for these patients. Furthermore, active research efforts are ongoing to develop therapeutic strategies that target dystrophin deficiency, such as gene replacement therapies, exon skipping, and readthrough therapy, as well as strategies that target secondary pathology of DMD, such as novel anti-inflammatory compounds, myostatin inhibitors, and cardioprotective compounds. Furthermore, longitudinal modeling approaches have been used to characterize the progression of MRI and functional endpoints for predictive purposes to inform Go/No Go decisions in drug development. This review showcases approved drugs or drug candidates along their development paths and also provides information on primary endpoints and enrollment size of Ph2/3 and Ph3 trials in the DMD space.

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“…Eteplirsen can skip the frameshift exon 51 and restore the splicing, transcription and translation of the following exons, which may alleviate a severe DMD phenotype, with an effect similar to Becker Muscular Dystrophy (BMD). However, it cannot permanently restore the dystrophin level because it has a short half-life in vivo [ 10 , 11 ], and full-length dystrophin protein restoration remains challenging.…”

Section: Introductionmentioning

confidence: 99%

Full-Length Dystrophin Restoration via Targeted Exon Addition in DMD-Patient Specific iPSCs and Cardiomyocytes

Xiao

Zhou

Wang

et al. 2022

IJMS

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Duchenne muscular dystrophy (DMD) is the most common fatal muscle disease, with an estimated incidence of 1/3500–1/5000 male births, and it is associated with mutations in the X-linked DMD gene encoding dystrophin, the largest known human gene. There is currently no cure for DMD. The large size of the DMD gene hampers exogenous gene addition and delivery. The genetic correction of DMD patient-derived induced pluripotent stem cells (DMD-iPSCs) and differentiation into suitable cells for transplantation is a promising autologous therapeutic strategy for DMD. In this study, using CRISPR/Cas9, the full-length dystrophin coding sequence was reconstructed in an exon-50-deleted DMD-iPSCs by the targeted addition of exon 50 at the junction of exon 49 and intron 49 via homologous-directed recombination (HDR), with a high targeting efficiency of 5/15, and the genetically corrected iPSCs were differentiated into cardiomyocytes (iCMs). Importantly, the full-length dystrophin expression and membrane localization were restored in genetically corrected iPSCs and iCMs. Thus, this is the first study demonstrating that full-length dystrophin can be restored in iPSCs and iCMs via targeted exon addition, indicating potential clinical prospects for DMD gene therapy.

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Pharmacology and toxicology of eteplirsen and SRP-5051 for DMD exon 51 skipping: an update

Cited by 32 publications

References 87 publications

Actin-Associated Proteins and Small Molecules Targeting the Actin Cytoskeleton

Actin-Associated Proteins and Small Molecules Targeting the Actin Cytoskeleton

Drug development progress in duchenne muscular dystrophy

Full-Length Dystrophin Restoration via Targeted Exon Addition in DMD-Patient Specific iPSCs and Cardiomyocytes

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