Genomic correction of familial cardiomyopathy in human engineered
                    cardiac tissues

Stillitano, Francesca; Turnbull, Irene C.; Karakikes, Ioannis; Nonnenmacher, Mathieu; Backeris, Peter; Hulot, Jean‐Sébastien; Kranias, Evangelia G.; Hajjar, Roger J.; Costa, Kevin D.

doi:10.1093/eurheartj/ehw307

Cited by 68 publications

(55 citation statements)

References 6 publications

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“…However, in contrast to constructs designed for surgical implantation [8], engineered tissues designed for in vitro applications, such as our organoids, may not require physiologic levels of function to be predictive and impactful, provided they can recapitulate cardiac-appropriate responses to treatments and interventions of interest. Prior cardiac tissue engineering studies have shown this in the context of arrhythmogenicity [33], contractility [14,34] and recapitulation of disease phenotypes [12,48]. This was further tested in the experiments that follow.…”

Section: Resultsmentioning

confidence: 98%

Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells

Keung²,

et al. 2018

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Tissue engineers and stem cell biologists have made exciting progress toward creating simplified models of human heart muscles or aligned monolayers to help bridge a longstanding gap between experimental animals and clinical trials. However, no existing human in vitro systems provide the direct measures of cardiac performance as a pump. Here, we developed a next-generation in vitro biomimetic model of pumping human heart chamber, and demonstrated its capability for pharmaceutical testing. From human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCM) embedded in collagen-based extracellular matrix hydrogel, we engineered a three-dimensional (3D) electro-mechanically coupled, fluid-ejecting miniature human ventricle-like cardiac organoid chamber (hvCOC). Structural characterization showed organized sarcomeres with myofibrillar microstructures. Transcript and RNA-seq analyses revealed upregulation of key Ca-handling, ion channel, and cardiac-specific proteins in hvCOC compared to lower-order 2D and 3D cultures of the same constituent cells. Clinically-important, physiologically complex contractile parameters such as ejection fraction, developed pressure, and stroke work, as well as electrophysiological properties including action potential and conduction velocity were measured: hvCOC displayed key molecular and physiological characteristics of the native ventricle, and showed expected mechanical and electrophysiological responses to a range of pharmacological interventions (including positive and negative inotropes). We conclude that such "human-heart-in-a-jar" technology could facilitate the drug discovery process by providing human-specific preclinical data during early stage drug development.

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Section: Resultsmentioning

confidence: 98%

Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells

Keung²,

et al. 2018

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“…(58) In another study using iPSCs, a mutation in phospholamban was shown to impair cardiomyocyte contractility and targeted genetic correction of the mutation rescued this defect. (59) These studies illustrate the power of combining iPSC and genome editing to understand the functional significance of genetic variation.…”

Section: Toward Novel Disease-specific Therapeuticsmentioning

confidence: 99%

Genetics of paediatric cardiomyopathies

Ware

2017

Current Opinion in Pediatrics

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Purpose of review Pediatric cardiomyopathy is a rare disease with a genetic basis. The purpose of this review is to discuss the current status of genetic findings in the pediatric cardiomyopathy population and present recent progress in utilizing this information for management and therapy. Recent findings With increased clinical genetic testing, an understanding of the genetic causes of cardiomyopathy is improving and novel causes are identified. Recent progress in identifying the scope of genetic variation in large population datasets has led to reassessment and refinement of our understanding of the significance of rare genetic variation. As a result, the stringency of variant interpretation has increased, at times leading to revision of previous mutation results. Transcriptome and epigenome studies are elucidating important pathways for disease progression and highlight similarities and differences from adult cardiomyopathy. Therapy targeted toward the underlying cause of cardiomyopathy is emerging for a number of rare syndromes such as Pompe and Noonan syndromes, and genome editing and induced pluripotent stem cells provide promise for additional precision medicine approaches. Summary Genetics is moving at a rapid pace in pediatric cardiomyopathy. Genetic testing is increasingly being incorporated into clinical care. While challenges in interpretation of rare genetic variation remains challenging, the opportunity to provide management and therapy targeted toward the underlying genetic cause is beginning to be realized.

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“…These same cells were used to engineer three dimensional human heart tissues and in this setting, more clear cut cardiomyopathic features were seen including reduced developed force that was improved after genetic correction 104 . In iPSC-derived cardiomyocytes and in hearts from PLN -mutation carriers, aggregates of phospholamban were seen in a perinuclear and cytoplasmic pattern suggesting that aggregated phospholamban contributes to the pathology possibly through aberrant autophagy 105 .…”

Section: Dcm Geneticsmentioning

confidence: 99%

Dilated Cardiomyopathy

McNally

Mestroni

2017

Circulation Research

535

303

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Nonischemic dilated cardiomyopathy often has a genetic etiology. Because of the large number of genes and alleles attributed to dilated cardiomyopathy, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at-risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of dilated cardiomyopathy, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to dilated cardiomyopathy and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of dilated cardiomyopathy, especially where arrhythmia risk is increased, and ultimately contribute to clinical management.

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Genomic correction of familial cardiomyopathy in human engineered cardiac tissues

Cited by 68 publications

References 6 publications

Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells

Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells

Genetics of paediatric cardiomyopathies

Dilated Cardiomyopathy

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