Dataset Information

Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study.

ABSTRACT: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant genetic disease mainly characterized by ptosis and dysphagia. We conducted a phase I/IIa clinical study (ClinicalTrials.gov NCT00773227) using autologous myoblast transplantation following myotomy in adult OPMD patients. This study included 12 patients with clinical diagnosis of OPMD, indication for cricopharyngeal myotomy, and confirmed genetic diagnosis. The feasibility and safety end points of both autologous myoblast transplantation and the surgical procedure were assessed by videoendoscopy in addition to physical examinations. Potential therapeutic benefit was also assessed through videoendoscopy and videofluoroscopy of swallowing, quality of life score, dysphagia grade, and a drink test. Patients were injected with a median of 178 million myoblasts following myotomy. Short and long-term (2 years) safety and tolerability were observed in all the patients, with no adverse effects. There was an improvement in the quality of life score for all 12 patients, and no functional degradation in swallowing was observed for 10 patients. A cell dose-dependant improvement in swallowing was even observed in this study. This trial supports the hypothesis that a local injection of autologous myoblasts in the pharyngeal muscles is a safe and efficient procedure for OPMD patients.

SUBMITTER: Perie S

PROVIDER: S-EPMC3978797 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study.

Périé Sophie S Trollet Capucine C Mouly Vincent V Vanneaux Valérie V Mamchaoui Kamel K Bouazza Belaïd B Marolleau Jean Pierre JP Laforêt Pascal P Chapon Françoise F Eymard Bruno B Butler-Browne Gillian G Larghero Jérome J St Guily Jean Lacau JL

Molecular therapy : the journal of the American Society of Gene Therapy 20130708 1

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant genetic disease mainly characterized by ptosis and dysphagia. We conducted a phase I/IIa clinical study (ClinicalTrials.gov NCT00773227) using autologous myoblast transplantation following myotomy in adult OPMD patients. This study included 12 patients with clinical diagnosis of OPMD, indication for cricopharyngeal myotomy, and confirmed genetic diagnosis. The feasibility and safety end points of both autologous myoblas ...[more]

PMID: 23831596

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Project description:BACKGROUND:Although dysphagia represents a hallmark manifestation of oculopharyngeal muscular dystrophy (OPMD), limited knowledge exists regarding the underlying nature of oropharyngeal swallowing impairments in this patient population. We aimed to delineate global pharyngeal dysphagia profiles in OPMD and identify the prevalence and physiologic associations of impairments in swallowing safety and efficiency. METHODS:Twenty-two individuals with OPMD completed a videofluoroscopic swallowing evaluation. Blinded raters completed validated scales of global dysphagia (dynamic imaging grade of swallowing toxicity, DIGEST), efficiency (normalized residue ratio scale, NRRS), and safety (penetration-aspiration scale, PAS). Degree of laryngeal vestibule closure and aspiration events were described. Descriptives and chi-squared analyses were conducted with alpha set at P < .05. KEY RESULTS:One hundred and thirty-four swallowing trials were analyzed. DIGEST scores revealed that 96% (n = 21) of participants demonstrated pharyngeal dysphagia (score >1). Presence of a cricopharyngeal bar was noted in 10 individuals. The predominant swallowing categorization across patients was safe and inefficient (51%) followed by unsafe and inefficient (32%). 77.3% demonstrated vallecular residue (NRRSv>0.07) and 90.1% piriform sinus residue (NRRSp > .20). 33% (n = 54) of swallows were unsafe (PAS>3) with 45 episodes of penetration and 9 episodes of aspiration. Aspiration occurred during the swallow in 100% of identified occurrences. Incomplete epiglottic inversion was associated with airway compromise and postswallow residue (P < .05). CONCLUSIONS & INFERENCES:These findings highlight the high prevalence of oropharyngeal swallowing impairments in both swallowing efficiency and safety. A high proportion of physiologic impairments in epiglottic inversion and laryngeal vestibule closure were noted that related to functional impairments in swallow safety and inefficiency.

Project description:Small non-coding microRNAs (miRNAs) are involved in the regulation of mRNA stability. Their features, including high stability and secretion to biofluids, make them attractive as potential biomarkers for diverse pathologies. This is the first study reporting miRNA as potential biomarkers for oculopharyngeal muscular dystrophy (OPMD), an adult-onset myopathy. We hypothesized that miRNA that is differentially expressed in affected muscles from OPMD patients is secreted to biofluids and those miRNAs could be used as biomarkers for OPMD. We first identified candidate miRNAs from OPMD-affected muscles and from muscles from an OPMD mouse model using RNA sequencing. We then compared the OPMD-deregulated miRNAs to the literature and, subsequently, we selected a few candidates for expression studies in serum and saliva biofluids using qRT-PCR. We identified 126 miRNAs OPMD-deregulated in human muscles, but 36 deregulated miRNAs in mice only (pFDR < 0.05). Only 15 OPMD-deregulated miRNAs overlapped between the in humans and mouse studies. The majority of the OPMD-deregulated miRNAs showed opposite deregulation direction compared with known muscular dystrophies miRNAs (myoMirs), which are associated. In contrast, similar dysregulation direction was found for 13 miRNAs that are common between OPMD and aging muscles. A significant age-association (p < 0.05) was found for 17 OPMD-deregulated miRNAs (13.4%), whereas in controls, only six miRNAs (1.4%) showed a significant age-association, suggesting that miRNA expression in OPMD is highly age-associated. miRNA expression in biofluids revealed that OPMD-associated deregulation in saliva was similar to that in muscles, but not in serum. The same as in muscle, miRNA expression levels in saliva were also found to be associated with age (p < 0.05). Moreover, the majority of OPMD-miRNAs were found to be associated with dysphagia as an initial symptom. We suggest that levels of specific miRNAs in saliva can mark muscle degeneration in general and dysphagia in OPMD.

Dataset Information

Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study.

Publications

Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study.

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