Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy

Kayalı, Refik; Ku, Jin‐Mo; Khitrov, Gregory; Jung, Michael E.; Приходько, Ольга Олексіївна; Bertoni, Carmen

doi:10.1093/hmg/dds223

Cited by 89 publications

(84 citation statements)

References 46 publications

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“…In addition, nonsense suppression therapy is also emerging as a therapy outside the eye. For example, in cystic fibrosis (7) and Duchenne muscular dystrophy mouse models (18), ataluren treatment lead to an approximately 25% increase in protein production, and this correlated with a similar improvement in functional studies. Thus, a moderate increase in gene expression is able to have a beneficial effect, but presumably the levels would need to be closer to 50% in the affected tissues for full rescue.…”

Section: Resultsmentioning

confidence: 95%

See 1 more Smart Citation

Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects

Gregory‐Evans¹,

Wang²,

Wasan³

et al. 2013

J. Clin. Invest.

102

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Aniridia is a congenital and progressive panocular condition with poor visual prognosis that is associated with brain, olfactory, and pancreatic abnormalities. Development of aniridia is linked with nonsense mutations that result in paired box 6 (PAX6) haploinsufficiency. Here, we used a mouse model of aniridia to test the hypothesis that manipulation of Pax6 dosage through a mutation-independent nonsense mutation suppression strategy would limit progressive, postnatal damage in the eye. We focused on the nonsense suppression drugs 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid (ataluren) and gentamicin. Remarkably, we demonstrated that nonsense suppression not only inhibited disease progression but also stably reversed corneal, lens, and retinal malformation defects and restored electrical and behavioral responses of the retina. The most successful results were achieved through topical application of the drug formulation START (0.9% sodium chloride, 1% Tween 80, 1% powdered ataluren, 1% carboxymethylcellulose), which was designed to enhance particle dispersion and to increase suspension viscosity. These observations suggest that the eye retains marked developmental plasticity into the postnatal period and remains sensitive to molecular remodeling. Furthermore, these data indicate that other neurological developmental anomalies associated with dosage-sensitive genetic mutations may be reversible through nonsense suppression therapeutics. IntroductionThe highly conserved paired box 6 (PAX6) transcription factor is pivotal to embryonic development and maintenance in the eye, brain, olfactory system, and pancreas (1). Genetic defects leading to haploinsufficiency of PAX6 cause congenital aniridia (2), a progressive panocular condition characterized by absence of iris tissue, corneal opacity, glaucoma, cataract, and foveal hypoplasia, which is also associated with brain, olfactory, and pancreatic abnormalities (3). While the genetic basis of congenital aniridia has been known for 2 decades, this has yet to be translated into preventative or corrective PAX6 treatment strategies, mainly because of PAX6 allelic heterogeneity, since more than 600 different mutations are known (4). Premature stop codons (PTCs) caused by nonsense mutations, splice-site mutations, and frameshift mutations account for 72% of all PAX6 disease-associated mutations (4); however, approximately 50% of all mutations are in-frame nonsense mutations. Therefore, we reasoned that a mutation-independent nonsense mutation suppression approach for in-frame PTCs (4) could be relevant for many patients if this could be achieved through a postnatal strategy. In this approach, during mRNA translation, a near-cognate aminoacyl tRNA is inserted into the polypeptide. Thus, as long as the PTC is not in a critical position for protein activity, then a functional protein would be produced with the potential to provide therapeutic benefit (5).We and others have previously undertaken proof-of-concept experiments showing that aminoglycosides promote readthr...

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Section: Resultsmentioning

confidence: 95%

“…Recently, the effectiveness of ataluren as a nonsense suppression agent has been questioned (17). Despite this, several in vivo studies (12,18), including this one, show beneficial efficacy of ataluren as a treatment strategy. Further research is needed to fully define the exact mechanism of action of this drug.…”

Section: Resultsmentioning

confidence: 99%

Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects

Gregory‐Evans¹,

Wang²,

Wasan³

et al. 2013

J. Clin. Invest.

102

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“…These compounds have been shown in both in vitro and in vivo models to alleviate disease pathogenesis by enhancing PTC read-through [119]. Examples include cystic fibrosis (CF) [120-131], Becker and Duchenne muscular dystrophy (BMD/DMD) [128, 129, 132-140], ataxia telangiectasia [139, 141, 142], Rett syndrome (RTT) [143-146], Usher syndrome type I (USH1) [147-149], Hurler syndrome (MPS1) [150-154], Maroteaux-Lamy syndrome (MPSVI) [155], carnitine palmitoyltransferase 1A (CPT1A) [156], hemophilia [157, 158], methylmalonic acidura (MMA) [159], neuronal ceroid lipofuscinosis (NCL) [114, 160, 161], spinal muscular atrophy (SMA) [162], peroxisome biogenesis disorder (PBD) [163, 164], obesity [165], poor drug metabolism [166], and cancer [151]. …”

Section: Current Therapeutic Approaches That Target Nonsense Mutatmentioning

confidence: 99%

Nonsense-mediated decay in genetic disease: Friend or foe?

Miller¹,

Pearce²

2014

Mutation Research/Reviews in Mutation Research

173

166

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Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA and the subsequent production of abnormal peptides. Messenger RNAs (mRNAs) are largely responsible for protein production, and mRNA quality control is particularly important for protecting the cell against the downstream effects of genetic mutations. Nonsense-mediated decay (NMD) is an evolutionarily conserved mRNA quality control system in all eukaryotes that degrades transcripts containing premature termination codons (PTCs). By degrading these aberrant transcripts, NMD acts to prevent the production of truncated proteins that could otherwise harm the cell through various insults, such as dominant negative effects or the ER stress response. Although NMD functions to protect the cell against the deleterious effects of aberrant mRNA, there is a growing body of evidence that mutation-, codon-, gene-, cell-, and tissue-specific differences in NMD efficiency can alter the underlying pathology of genetic disease. In addition, the protective role that NMD plays in genetic disease can undermine current therapeutic strategies aimed at increasing the production of full-length functional protein from genes harboring nonsense mutations. Here, we review the normal function of this RNA surveillance pathway and how it is regulated, provide current evidence for the role that it plays in modulating genetic disease phenotypes, and how NMD can be used as a therapeutic target.

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“…One of these molecules is Ataluren (Translarna, former PTC124), a nonaminoglycoside without antibacterial activity [11]. The expression of dystrophin is upregulated in skeletal muscles (including diaphragm) and hearth of mdx mice treated with Ataluren [56,57]. Two doses of Ataluren in patients with nonsense mutation were demonstrated efficacious and well tolerated during a phase IIb clinical trial [58].…”

Section: Alternative Approachesmentioning

confidence: 99%

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

Chiappalupi

Salvadori

Luca

et al. 2017

JFMK

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Duchenne muscular dystrophy (DMD) is a lethal X-linked pathology due to lack of dystrophin and characterized by progressive muscle degeneration, impaired locomotion and premature death. The chronic presence of inflammatory cells, fibrosis and fat deposition are hallmarks of DMD muscle tissue. Many different therapeutic approaches to DMD have been tested, including cell-based and gene-based approaches, exon skipping, induction of expression of the dystrophin paralogue, utrophin, and, most recently the application of the CASPR/Cas9 genome editing system. However, corticosteroid treatment remains the gold standard therapy, even if corticosteroids have shown multiple undesirable side effects. Sertoli cells (SeC) have long been known for their ability to produce immunomodulatory and trophic factors, and have been used in a plethora of experimental models of disease. Recently, microencapsulated porcine SeC (MC-SeC) injected intraperitoneally in dystrophic mice produced morphological and functional benefits in muscles thanks to their release into the circulation of anti-inflammatory factors and heregulin β1, a known inducer of utrophin expression, thus opening a new avenue in the treatment of DMD. In order to stress the potentiality of the use of MC-SeC in the treatment of DMD, here, we examine the principal therapeutic approaches to DMD, and the properties of SeC (either nude or encapsulated into alginate-based microcapsules) and their preclinical and clinical use. Finally, we discuss the potential and future development of this latter approach.Keywords: Duchenne muscular dystrophy; therapeutic approaches; Sertoli cell; muscle inflammation; myopathies; encapsulation; biomaterials Duchenne Muscular Dystrophy (DMD)Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy. Muscular dystrophies are a group of inherited muscle diseases characterized by mutations in specific genes and resulting in muscle degeneration, impaired locomotion and premature death [1,2]. DMD is an X-linked recessive pathology caused by mutations in the dystrophin gene (DMD) usually resulting in the complete absence of this protein. Dystrophin is an essential component of the dystrophin-associated protein complex (DAPC) at the sarcolemma, a complex that ensures the structural and functional integrity of the myofibers during contraction representing a mechanical link between the intracellular cytoskeleton and the extracellular matrix. Absence of dystrophin or other components of the DAPC compromises the integrity of the DAPC itself leading to a susceptibility of myofibers to degeneration

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Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy

Cited by 89 publications

References 46 publications

Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects

Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects

Nonsense-mediated decay in genetic disease: Friend or foe?

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

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