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A Precision Medicine Approach to the Rescue of Function on Malignant Calmodulinopathic Long-QT Syndrome.
Limpitikul, Worawan B; Dick, Ivy E; Tester, David J; Boczek, Nicole J; Limphong, Pattraranee; Yang, Wanjun; Choi, Myoung Hyun; Babich, Jennifer; DiSilvestre, Deborah; Kanter, Ronald J; Tomaselli, Gordon F; Ackerman, Michael J; Yue, David T.
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  • Limpitikul WB; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • Dick IE; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • Tester DJ; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • Boczek NJ; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • Limphong P; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • Yang W; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • Choi MH; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • Babich J; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • DiSilvestre D; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • Kanter RJ; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • Tomaselli GF; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • Ackerman MJ; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
  • Yue DT; From the Calcium Signals Laboratory, Department of Biomedical Engineering (W.B.L., I.E.D., W.Y., M.H.C., J.B., D.T.Y.) and Division of Cardiology, Department of Medicine (P.L., D.D., G.F.T.), The Johns Hopkins University School of Medicine, Baltimore, MD; Department of Physiology, The University of
Circ Res ; 120(1): 39-48, 2017 Jan 06.
Article en En | MEDLINE | ID: mdl-27765793
ABSTRACT
RATIONALE Calmodulinopathies comprise a new category of potentially life-threatening genetic arrhythmia syndromes capable of producing severe long-QT syndrome (LQTS) with mutations involving CALM1, CALM2, or CALM3. The underlying basis of this form of LQTS is a disruption of Ca2+/calmodulin (CaM)-dependent inactivation of L-type Ca2+ channels.

OBJECTIVE:

To gain insight into the mechanistic underpinnings of calmodulinopathies and devise new therapeutic strategies for the treatment of this form of LQTS. METHODS AND

RESULTS:

We generated and characterized the functional properties of induced pluripotent stem cell-derived cardiomyocytes from a patient with D130G-CALM2-mediated LQTS, thus creating a platform with which to devise and test novel therapeutic strategies. The patient-derived induced pluripotent stem cell-derived cardiomyocytes display (1) significantly prolonged action potentials, (2) disrupted Ca2+ cycling properties, and (3) diminished Ca2+/CaM-dependent inactivation of L-type Ca2+ channels. Next, taking advantage of the fact that calmodulinopathy patients harbor a mutation in only 1 of 6 redundant CaM-encoding alleles, we devised a strategy using CRISPR interference to selectively suppress the mutant gene while sparing the wild-type counterparts. Indeed, suppression of CALM2 expression produced a functional rescue in induced pluripotent stem cell-derived cardiomyocytes with D130G-CALM2, as shown by the normalization of action potential duration and Ca2+/CaM-dependent inactivation after treatment. Moreover, CRISPR interference can be designed to achieve selective knockdown of any of the 3 CALM genes, making it a generalizable therapeutic strategy for any calmodulinopathy.

CONCLUSIONS:

Overall, this therapeutic strategy holds great promise for calmodulinopathy patients as it represents a generalizable intervention capable of specifically altering CaM expression and potentially attenuating LQTS-triggered cardiac events, thus initiating a path toward precision medicine.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de QT Prolongado / Calmodulina / Células Madre Pluripotentes Inducidas / Medicina de Precisión Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Female / Humans Idioma: En Revista: Circ Res Año: 2017 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de QT Prolongado / Calmodulina / Células Madre Pluripotentes Inducidas / Medicina de Precisión Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Female / Humans Idioma: En Revista: Circ Res Año: 2017 Tipo del documento: Article