Selective Vacuolar Degeneration in Dystrophin-Deficient Canine Purkinje Fibers Despite Preservation of Dystrophin-Associated Proteins With Overexpression of Dp71

Urasawa, Nobuyuki; Wada, Mitsuru; Motomura, Noboru; Yuasa, Katsutoshi; Shimatsu, Yoshiki; Wakao, Yoshito; Yuasa, Shigeki; Sendo, Toshiaki; Nonaka, Ikuya; Nakamura, Akinori; Takeda, Shin’ichi

doi:10.1161/circulationaha.107.739326

Cited by 36 publications

(41 citation statements)

References 55 publications

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“…We examined whether rescued dystrophin expression can ameliorate vacuole degeneration in CXMD J dogs. Cardiac Purkinje fibers were identified as having a larger diameter and fainter stainability compared with working myocardium, as observed on transverse sections following H&E staining, as previously described (22). Immunohistochemistry and H&E staining of serial sections revealed reduced vacuole degeneration in cardiac Purkinje fibers, which was accompanied by the recovery of dystrophin expression in the same fibers, of the systemically treated CXMD J dogs (ID nos.…”

Section: Recovery Of Dystrophin Expression and Amelioration Of Vacuolementioning

confidence: 69%

“…However, it is still unclear if cardiac conduction abnormalities as detected by electrocardiography (ECG) in DMD patients can be improved by the rescue of dystrophin expression in the heart. Although dystrophic mouse models show few cardiac abnormalities (20), dystrophic dog models, particularly CXMD J dogs, manifest obvious cardiac symptoms, including distinct Q-waves and increased Q/R ratio, which indicate a cardiac conduction abnormality, in ECG (21), and vacuole degeneration in cardiac Purkinje fibers by 4 mo of age (22). We report here that systemic treatment with a cocktail of peptide-conjugated morpholinos (PPMOs) (18) (Fig.…”

Section: Significancementioning

confidence: 86%

“…CXMD J dogs have been reported to exhibit vacuole degeneration in cardiac Purkinje fibers, a histopathological finding also seen in DMD patients (22)(23)(24). We examined whether rescued dystrophin expression can ameliorate vacuole degeneration in CXMD J dogs.…”

Section: Recovery Of Dystrophin Expression and Amelioration Of Vacuolementioning

confidence: 99%

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Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy

Echigoya

Nakamura

Nagata

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Duchenne muscular dystrophy (DMD) is a lethal genetic disorder caused by an absence of the dystrophin protein in bodywide muscles, including the heart. Cardiomyopathy is a leading cause of death in DMD. Exon skipping via synthetic phosphorodiamidate morpholino oligomers (PMOs) represents one of the most promising therapeutic options, yet PMOs have shown very little efficacy in cardiac muscle. To increase therapeutic potency in cardiac muscle, we tested a nextgeneration morpholino: arginine-rich, cell-penetrating peptideconjugated PMOs (PPMOs) in the canine X-linked muscular dystrophy in Japan (CXMD J ) dog model of DMD. A PPMO cocktail designed to skip dystrophin exons 6 and 8 was injected intramuscularly, intracoronarily, or intravenously into CXMD J dogs. Intravenous injections with PPMOs restored dystrophin expression in the myocardium and cardiac Purkinje fibers, as well as skeletal muscles. Vacuole degeneration of cardiac Purkinje fibers, as seen in DMD patients, was ameliorated in PPMO-treated dogs. Although symptoms and functions in skeletal muscle were not ameliorated by i.v. treatment, electrocardiogram abnormalities (increased Q-amplitude and Q/R ratio) were improved in CXMD J dogs after intracoronary or i.v. administration. No obvious evidence of toxicity was found in blood tests throughout the monitoring period of one or four systemic treatments with the PPMO cocktail (12 mg/kg/injection). The present study reports the rescue of dystrophin expression and recovery of the conduction system in the heart of dystrophic dogs by PPMO-mediated multiexon skipping. We demonstrate that rescued dystrophin expression in the Purkinje fibers leads to the improvement/prevention of cardiac conduction abnormalities in the dystrophic heart. Duchenne muscular dystrophy | exon skipping | peptide-conjugated morpholinos | cardiac Purkinje fibers | dystrophic dog model

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Section: Recovery Of Dystrophin Expression and Amelioration Of Vacuolementioning

confidence: 69%

Section: Significancementioning

confidence: 86%

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Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy

Echigoya

Nakamura

Nagata

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The PAS stain of the Purkinje fibers showed PASpositive granular material in the cytoplasm and in some vacuoles consistent with glycogen (McManus 1948). However, Urasawa et al (2008) also describe a colony of dogs with a form of X-linked muscular dystrophy in which a different FIGURE 8.-Chorda tendinea and left papillary muscle, male dog. Dilated lymphatic vessels and blood vessels are present at the point of insertion of a chorda tendinea into the papillary muscle.…”

Section: Discussionmentioning

confidence: 93%

Incidental Histopathological Findings in Hearts of Control Beagle Dogs in Toxicity Studies

Bodié

Decker

2013

Toxicol Pathol

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In preclinical studies of pharmaceutical agents, the beagle dog is a commonly used model for the detection of cardiotoxicity. Incidental findings, postmortem changes, and artifacts must be distinguished histopathologically from test item-related findings in the heart. In this retrospective analysis, cardiac sections from 88 control beagles (41 male, 47 female; ages 5-18 months) in preclinical studies were examined histopathologically. The most common finding was thickening of the tunica media of intramural coronary arteries, most likely a postmortem change. The second most common finding was the presence of vacuoles within Purkinje fibers. Dilated lymphatic and blood vessels at the insertion of chordae tendineae were noted more commonly in males than in females and were considered a normal anatomic feature. Mesothelial-lined papillary fronds along the epicardial surface of the atria were present in several dogs, as were small infiltrates of inflammatory cells usually within the myocardium. In summary, control beagles' hearts frequently have incidental findings that must be differentiated from test item-related pathologic changes. Historical control data can be useful for the interpretation of incidental and test item-related findings in the beagle heart.

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“…Utrophin has been confirmed in many of the species in which dystrophin has been identified (4,30,31).…”

Section: Introductionmentioning

confidence: 95%

Zebrafish dystrophin and utrophin genes: Dissecting transcriptional expression during embryonic development

Lai

Lan²,

Leong³

et al. 2011

Int J Mol Med

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Abstract. Some genes can encode multiple overlapping transcripts, and this can result in challenges in identifying transcript-specific developmental expression profiles where tools such as RNA in situ hybrisations are inapplicable. Given this difficulty, we have undertaken a preliminary analysis of the developmental expression profile of selected transcripts of the dystrophin and utrophin genes of the zebrafish (Danio rerio) by targeting unique and common regions of each of these transcripts. The dystrophin and utrophin genes of zebrafish were identified by bioinformatic analysis and the dystrophin gene predictions were confirmed by transcript sequencing. These data enabled primer pairs to be designed in order to determine the expression profiles of unique, but overlapping transcripts, throughout embryonic development using quantitative real time reverse transcription PCR (qRT-PCR). The data indicated the early expression of the short carboxyl-terminal dystrophin transcript, with expression of the full length muscle transcript occurring during myogenesis. Importantly, a composite of these two profiles appeared to comprise the major transcriptional load of the zebrafish dystrophin gene. In contrast, utrophin gene expression was dominated by the full length transcript throughout embryogenesis. The approach described here provided a means by which a gene's transcriptional complexity can be deconvoluted to reveal transcriptional diversity during embryogenesis. This approach, however, required the identification of unique regions for transcript-specific targeting, and an appreciation of alternative splicing events that may compromise the design of primers for qRT-PCR.

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Selective Vacuolar Degeneration in Dystrophin-Deficient Canine Purkinje Fibers Despite Preservation of Dystrophin-Associated Proteins With Overexpression of Dp71

Cited by 36 publications

References 55 publications

Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy

Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy

Incidental Histopathological Findings in Hearts of Control Beagle Dogs in Toxicity Studies

Zebrafish dystrophin and utrophin genes: Dissecting transcriptional expression during embryonic development

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