Abstract P2008: Hypertrophic Cardiomyopathy Treatment Using Ultrasound And Microbubbles
Notice bibliographique
Résumé
Introduction: Hypertrophic cardiomyopathy is a disease characterized by the abnormal growth of cardiomyocytes (CMs), a marker of which is the early downregulation of miR-1. The delivery of miR-1 to hypertrophic CMs presents as a promising treatment strategy, however there are still limitations in the safe and efficient delivery of gene therapeutics.Ultrasound (US) and microbubbles is an emerging approach to site-specific gene delivery. Microbubbles have long been employed in clinical cardiology as a diagnostic contrast agent. Recent work has demonstrated that under specific conditions, they are capable of forming temporary pores on neighboring cell membranes, allowing the delivery of otherwise impermeable macromolecules. This presents an exciting approach to the treatment of cardiovascular disease (CVD) as a targeted and inherently image-guided therapeutic delivery platform. Objective: The goal of this study is to determine the feasibility of viable US and microbubble mediated delivery of miR-1 to hypertrophic CMs with a view towards reversing the disease. Secondly, we aim to show a correlation between bubble echoes and resulting gene delivery to introduce clinical metrics for the translation of this technique. Methods: CMs were harvested from neonatal rat pups (1-3 days old) and hypertrophied using phenylephrine (100μM). Suspension of healthy or diseased CMs, microbubbles and free miR-1 were placed in a chamber within a 37°C degassed water bath. These samples were insonicated at a mechanical index (MI) ranging from 0.063-0.25 for 2 minutes (20 cycles; 5 kHz PRF) and bubble echoes were recorded via a co-aligned transducer to be processed offline. miR-1 delivery was confirmed with RT-qPCR, cell viablity assesed with MTT, protein expression was measured by immunoblotting and cell size via microscopy. All experiments preformed are at least n=2 independent samples. Result and Conclusion: Treated healthy and diseased CMs demonstrate an upregulation in miR-1 with increasing MI, from 0.063 to 0.188. At MI=0.12, a 2.22 and 1.95-fold increase in miR-1 was shown in diseased and healthy CMs respectively ( p= 0.07, p= 0.02) while maintaining viability (86% and 96% respectively). These miR-1 levels begin to show the reversal of hypertrophy as quantified by increases in target protein expression (1.93-fold in TWF1; 1.38-fold in MEF2A; 1.36-fold in CX43) and cell size decrease (16%, p =0.035) back towards heathy levels. Echo data highlights that relative miR-1 expression positively correlates with bubble disruption ( r =0.76, p =0.04), suggesting a means by which treatment efficiency can be monitored in a clinical setting.In conclusion, we demonstrated that US and microbubbles can be used to successfully delivery miR-1 to CMs, with the potential to reverse the disease phenotype. These findings demonstrate the feasibility of US as an image-guided delivery method for molecular therapeutics in CVD.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».