Search

Given that numerous genetic disorders, driven by diverse pathogenic mechanisms, may be amenable to recombinant adeno-associated virus (rAAV)-delivered gene therapies, the sustained innovation of rAAV-based therapeutic modalities is crucial. The progression and severity of genetic diseases can be reduced by targeting the toxic transcripts of a defective gene using microRNA (miRNA)-based miQURE technology delivered within an AAV vector. By adapting the delivered cassette, it may be possible to simultaneously regulate the expression profile of multiple genes involved in the pathogenesis of complex genetic diseases. The established miQURE gene silencing strategy was expanded by concatenating several miQURE molecules in a single construct, resulting in the novel linQURE platform. Here, a proof of mechanism is established by demonstrating that linQURE technology enables the concomitant expression of two synthetic miRNAs in vitro and in vivo, allowing more efficient downregulation of their disease-causing mRNA targets. This approach supports the development of multi-targeting therapeutic strategies, enabling gene therapy products to adapt to more complex multigenic indications, thus expanding the toolbox of readily available gene therapies.

Objective: Perform the validation and psychometric evaluation of the Brazilian-Portuguese translation of the Functional Outcome of Sleep Questionnaire 10 (FOSQ10). Materials and methods: 182 patients (65 females 48.3 ± 14.4 years and 117 males 46.9 ± 12.4 years), were evaluated by sleep physicians suspected of having Obstructive Sleep Apnea, underwent polysomnography and completed the FOSQ-10 and the Epworth Sleepiness Scale. APA & NCME, 2014 was used to validate the data as the American Educational Research Association recommended. Results: Quality indicators such as Bartlett's test of sphericity (χ2 = 1108.2; gL = 45; p = 0.000010) and KMO (0.83), and adherence measures, attest to the quality of the model. The indicators TLI (0.97), CFI (0.98), and RMSEA (0.04) fall within the expected values. Using the Eigenvalue > 1 technique, two factors explain 53% and 13.3% of the variances. In the Parallel Analysis technique, a single factor explained 59.4653% of the random variance, and the Unidimensionality indicators UniCo = 0.921, ECV = 0.822, and MIREAL = 0.253, were supported. Construct Validity: reliability coefficients Cronbach’s α = 0.87, McDonald’s ordinal Omega index 0.9, and the Composite Reliability 0.891 were satisfactory. Convergent validity: There was a significant Spearman correlation between FOSQ-10 and the Epworth Sleepiness Scale (r = 0.364 [−0.487; −0.226]). Criterion validity: Was not possible to differentiate the groups based on the severity of AHI using FOSQ-10P. Conclusions: The Brazilian translation of FOSQ-10 is valid and reliable for identifying significant effects of excessive daytime sleepiness in patients with Obstructive Sleep Apnea. Level of evidence: 2.

A gene-silencing platform (miQURE) has been developed and successfully used to deliver therapeutic microRNA (miRNA) to the brain, reducing levels of neurodegenerative disease-causing proteins/RNAs via RNA interference and improving the disease phenotype in animal models. This study evaluates the use of miQURE technology to deliver therapeutic miRNA for liver-specific indications. Angiopoietin-like 3 (ANGPTL3) was selected as the target mRNA because it is produced in the liver and because loss-of-function ANGPTL3 mutations and/or pharmacological inhibition of ANGPTL3 protein lowers lipid levels and reduces cardiovascular risk. Overall, 14 candidate miRNA constructs were tested in vitro, the most potent of which (miAngE) was further evaluated in mice. rAAV5-miAngE led to dose-dependent (≤−77%) decreases in Angptl3 mRNA in WT mice with ≤−90% reductions in plasma ANGPTL3 protein. In dyslipidemic APOE∗3-Leiden.CETP mice, AAV5-miAngE significantly reduced cholesterol and triglyceride levels vs. vehicle and scrambled (miSCR) controls when administrated alone, with greater reductions when co-administered with lipid-lowering therapy (atorvastatin). A significant decrease in total atherosclerotic lesion area (−58% vs. miSCR) was observed in AAV5-miAngE-treated dyslipidemic mice, which corresponded with the maintenance of a non-diseased plaque phenotype and reduced lesion severity. These results support the development of this technology for liver-directed indications.

Objective: To compare polysomnographic parameters with others from the literature in order to provide more accurate information about Rapid Maxillary Expansion (RME) for treating Obstructive Sleep Apnea (OSA) in children, through raising the question: Is RME a good option for treating OSA in children? Prevention of mouth breathing during children's growth remains a challenge with significant clinical consequences. In addition, OSA induces anatomofunctional changes during the critical period of craniofacial growth and development. Methods: The Medline, PubMed, EMBASE, CINAHL, Web of Science, SciELO and Scopus electronic databases were searched up to February 2021 for systematic reviews with meta-analysis in the English language. Among 40 studies on RME for treating OSA in children, we selected seven in which polysomnographic measurements of the Apnea-Hypopnea Index (AHI) had been made. Data were extracted and examined in order to clarify whether any consistent evidence exists for indicating RME as a treatment for OSA in children. Results: We found no consistent evidence favoring RME for long-term treatment of OSA in children. All the studies presented considerable heterogeneity due to variability of age and length of follow-up. Conclusion: Through this umbrella review, the need for methodologically better studies on RME is supported. Moreover, it can be considered that RME is not recommended for treating OSA in children. Further studies and more evidence identifying early signs of OSA are necessary in order to achieve consistent healthcare practice.

Objectives: To investigate the evidence on the association between ankyloglossia and obstructive sleep apnea. Methods: An integrative literature review was carried out in the databases. Observational and interventional studies that assessed the lingual frenulum in children with sleep-disordered breathing were included. As exclusion criteria: studies in animals, in vitro, letters to the editor, expert opinions, other reviews. The selected articles were analyzed regarding the study design, sample, characterization of the lingual frenulum and sleep assessment, in addition to the main results and conclusions. Results: Ninety-seven articles were identified, but only 4 met the inclusion criteria. Two retrospective studies concluded that the untreated shortened lingual frenulum at birth is associated with obstructive sleep apnea. A prospective study concluded that there was an improvement in speech and deglutition after lingual frenectomy, in addition to improved sleep. A retrospective cohort concluded that lingual frenuloplasty combined with myofunctional therapy is effective in the treatment of snoring and mouth breathing. Conclusion: The studies included in this review contribute to corroborate the association between ankyloglossia and obstructive sleep apnea.