Cricopharyngeal Myotomy in the Treatment of Oculopharyngeal Muscular Dystrophy

Gómez-Torres, Antonio; Jiménez, Antonio Abrante; Infante, Eloy Rivas; Bueno, Alicia Menoyo; Zamora, Isabel Tirado; Ortega, Francisco

doi:10.1016/j.otoeng.2012.11.009

Cited by 6 publications

(5 citation statements)

References 18 publications

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“…We focused on laryngeal pharynx muscles, including thyropharyngeus (TP) and cricopharyngeus (CP) muscles ( Supplementary Figure S4A ), which are involved in several pharyngeal pathologies including cricopharyngeal spasm ( Arenaz Búa et al, 2015 ) and oculopharyngeal muscular dystrophy ( Gómez-Torres et al, 2012 ). Although pharyngeal muscles are not derived from Pax3 + myogenic progenitor as limb muscles are ( Supplementary Figure S4B ), both craniofacial and limb satellite cells (SCs) are distinguished by the expression of the paired-box/homeodomain transcription factor, PAX7.…”

Section: Resultsmentioning

confidence: 99%

Fibroadipogenic Progenitors Regulate the Basal Proliferation of Satellite Cells and Homeostasis of Pharyngeal Muscles via HGF Secretion

Kim

Lim

et al. 2022

Front. Cell Dev. Biol.

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Skeletal muscle stem cells, known as satellite cells (SCs), are quiescent in normal adult limb muscles. Injury stimulates SC proliferation, differentiation, and fusion to regenerate muscle structure. In pharyngeal muscles, which are critical for swallowing foods and liquids, SCs proliferate and fuse in the absence of injury. It is unknown what factors drive increased basal activity of pharyngeal SCs. Here, we determined how niche factors influence the status of pharyngeal versus limb SCs. In vivo, a subset of pharyngeal SCs present features of activated SCs, including large cell size and increased mitochondrial content. In this study, we discovered that the pharyngeal muscle contains high levels of active hepatocyte growth factor (HGF), which is known to activate SCs in mice and humans. We found that fibroadipogenic progenitors (FAPs) are the major cell type providing HGF and are thus responsible for basal proliferation of SCs in pharyngeal muscles. Lastly, we confirmed the critical role of FAPs for pharyngeal muscle function and maintenance. This study gives new insights to explain the distinctive SC activity of pharyngeal muscles.

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Section: Resultsmentioning

confidence: 99%

Fibroadipogenic Progenitors Regulate the Basal Proliferation of Satellite Cells and Homeostasis of Pharyngeal Muscles via HGF Secretion

Kim

Lim

et al. 2022

Front. Cell Dev. Biol.

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“…Not surprisingly, current treatments for dysphagia in individuals with OPMD focus on mitigating UES hypertonicity. Surgical interventions include cricopharyngeal myotomy, cricopharyngeal dilatation and/or cricopharyngeal botulinum toxin injection . Because UES opening is the target of these interventions, these procedures do not impact other mechanisms that contribute to oropharyngeal dysphagia including impaired lingual propulsion, pharyngeal contraction and laryngeal vestibule closure .…”

Section: Introductionmentioning

confidence: 99%

“…Because UES opening is the target of these interventions, these procedures do not impact other mechanisms that contribute to oropharyngeal dysphagia including impaired lingual propulsion, pharyngeal contraction and laryngeal vestibule closure . As a result, current interventions are reported to yield disappointing functional improvements in oropharyngeal swallowing with percutaneous endoscopic gastronomy (PEG) tubes recommended for means of alternative nutrition in end stages of disease as swallow function progressively declines . This is particularly impactful as severity of dysphagia is associated with pulmonary sequelae and exacerbated disease prognosis…”

Section: Introductionmentioning

confidence: 99%

Oropharyngeal dysphagia profiles in individuals with oculopharyngeal muscular dystrophy

Tabor

Plowman

Romero-Clark

et al. 2017

Neurogastroenterology Motil

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“…The disease primarily involves some localized muscle groups like the external ocular region (which causes eyelid drooping) and muscles of the pharyngeal area (that severely affects swallowing) but at a later stage muscles of the limbs are also affected. Currently there is no cure for such disease and the only possible treatments are based on surgical interventions to correct ptosis and dysphagia (6)(7)(8)(9). OPMD is due to an expansion of GCG triplets in the exon 1 of the poly(A) binding protein nuclear 1 (PABPN1) gene (10).…”

Section: Introductionmentioning

confidence: 99%

Established PABPN1 intranuclear inclusions in OPMD muscle can be efficiently reversed by AAV-mediated knockdown and replacement of mutant expanded PABPN1

Malerba

Klein

Lu-Nguyen

et al. 2019

Human Molecular Genetics

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Abstract Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant late-onset muscular dystrophy affecting approximately 1:100 000 individuals in Europe. OPMD is mainly characterized by progressive eyelid drooping (ptosis) and dysphagia although muscles of the limbs can also be affected late in life. This muscle disease is due to a trinucleotide repeat expansion in the polyA-binding protein nuclear-1 gene. Patients express a protein with an 11–18 alanine tract that is misfolded and prone to form intranuclear inclusions, which are the hallmark of the disease. Other features of OPMD include muscle fibrosis and atrophy in affected muscles. Currently, no pharmacological treatments are available, and OPMD patients can only be referred to surgeons for cricopharyngeal myotomy or corrective surgery of extraocular muscles to ease ptosis. We recently tested a two-AAV `silence’ and `replace’ vector-based gene therapy treatment in a mouse model of OPMD. We demonstrate here that this gene therapy approach can revert already established insoluble aggregates and partially rescues the muscle from atrophy, which are both crucially important since in most cases OPMD patients already have an established disease when diagnosed. This strategy also prevents the formation of muscle fibrosis and stabilizes the muscle strength to the level of healthy muscles. Furthermore, we show here that similar results can be obtained using a single AAV vector incorporating both the `silence’ and `replace’ cassettes. These results further support the application of a gene therapy approach as a novel treatment for OPMD in humans.

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Cricopharyngeal Myotomy in the Treatment of Oculopharyngeal Muscular Dystrophy

Cited by 6 publications

References 18 publications

Fibroadipogenic Progenitors Regulate the Basal Proliferation of Satellite Cells and Homeostasis of Pharyngeal Muscles via HGF Secretion

Fibroadipogenic Progenitors Regulate the Basal Proliferation of Satellite Cells and Homeostasis of Pharyngeal Muscles via HGF Secretion

Oropharyngeal dysphagia profiles in individuals with oculopharyngeal muscular dystrophy

Established PABPN1 intranuclear inclusions in OPMD muscle can be efficiently reversed by AAV-mediated knockdown and replacement of mutant expanded PABPN1

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