Asymmetric septal hypertrophy in heterozygous cMyBP-C null mice

Carrier, Lucie; Knöll, Ralph; Vignier, Nicolas; Keller, Dagmar I.; Bausero, Pedro; Prudhon, Bernard; Isnard, Richard; Ambroisine, Marie-Lory; Fiszman, Marc; Ross, John; Schwartz, Ketty; Chien, Kenneth R.

doi:10.1016/j.cardiores.2004.04.009

Cited by 130 publications

(180 citation statements)

References 36 publications

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“…Yet, we believe that prevention is the more realistic scenario in the patient group we would like to target with the gene therapy approach, namely infants with severe homozygous or compound heterozygous mutations who quickly develop a therapy-resistant form of systolic heart failure 14,[16][17][18][19][20] . Second, mouse models including our KI model clearly differ from human HCM in that they show a much milder phenotype, generally only at the homozygous state 8,40,41 . In fact, our KI mice, although likely the best murine HCM model available, have a normal life expectancy and, as shown also in this study, LVH and the decrease in LV contractile function remain stable over time.…”

Section: Discussionmentioning

confidence: 99%

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

et al. 2014

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Homozygous or compound heterozygous frameshift mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) cause neonatal hypertrophic cardiomyopathy (HCM), which rapidly evolves into systolic heart failure and death within the first year of life. Here we show successful long-term Mybpc3 gene therapy in homozygous Mybpc3-targeted knock-in (KI) mice, which genetically mimic these human neonatal cardiomyopathies. A single systemic administration of adeno-associated virus (AAV9)-Mybpc3 in 1-day-old KI mice prevents the development of cardiac hypertrophy and dysfunction for the observation period of 34 weeks and increases Mybpc3 messenger RNA (mRNA) and cMyBP-C protein levels in a dose-dependent manner. Importantly, Mybpc3 gene therapy unexpectedly also suppresses accumulation of mutant mRNAs. This study reports the first successful long-term gene therapy of HCM with correction of both haploinsufficiency and production of poison peptides. In the absence of alternative treatment options except heart transplantation, gene therapy could become a realistic treatment option for severe neonatal HCM.

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Section: Discussionmentioning

confidence: 99%

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

et al. 2014

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“…MyBP-C's role in cardiac function is still widely unknown but is suspected to contribute to ␤-adrenergic-mediated gains in function (105,357,771,772,839,840), myofilament Ca 2ϩ sensitivity (102,331,365,542), and length-dependent changes in myofilament Ca 2ϩ sensitivity (105,358). Additionally, MyBP-C must play a critical role in normal cardiac function as 20 -30% of inherited HCM cases are attributed to mutations in the gene that encodes for MyBP-C (226,638).…”

Section: Thick Filament Accessory Proteins: C-protein (Mybp-c)mentioning

confidence: 99%

“…For instance, a clinical study reported no detectable levels of MyBP-C in HCM patients with MyBP-C mutant alleles (760), suggesting that the mutated MyBP-C is unstable with a pathogenic mechanism leaning towards one of haploinsufficiency. A heterozygous MyBP-C null mouse model also lends some support to the mechanism of haploinsufficiency as a knockout of one MyBP-C allele resulted in a slight but significant decrease in total MyBP-C content (102). In contrast, the development of transgenic mouse models that have two-to eightfold overexpression of either wild-type MyBP-C or an HCM-linked truncated MyBP-C demonstrated that MyBP-C stoichiometry is conserved and that the truncated MyBP-C is indeed stable (990).…”

Section: Thick Filament Accessory Proteins: C-protein (Mybp-c)mentioning

confidence: 99%

“…However, MyBP-C knockout and phosphorylation mimetic transgenic mouse models have been used to examine the role of MyBP-C phosphorylation as it pertains to the regulation of cardiac muscle contractility. Knockout models suggest that PKAmediated phosphorylation of MyBP-C contributes to both the magnitude of desensitization of the myofilaments to Ca 2ϩ (102) and enhanced cross-bridge cycling during ␤-adrenergic stimulation (345,357,434). A phosphomimetic transgenic mouse was designed using aspartic acid substitutions and showed that constitutive phosphorylation of MyBP-C conferred cardioprotection during ischemia-reperfusion injury (772).…”

Section: Thick Filament Accessory Proteins: C-protein (Mybp-c)mentioning

confidence: 99%

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Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca2+handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.

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“…One exception is a deletion of proximal myosin-binding protein-C sequences; heterozygous mutant mice exhibited normal heart structure while homozygous mutant mice developed hypertrophy (15). Remarkably, while most heterozygous mouse models with a mutation in myosin heavy chain, myosin-binding protein-C, or troponin T developed HCM (16)(17)(18), homozygous mutant mice (19,20) developed DCM with fulminant heart failure and, in some cases, premature death. These mouse studies might indicate that HCM, DCM, and heart failure reflect gradations of a single molecular pathway.…”

Section: Force Generation and Propagationmentioning

confidence: 99%