A Precision Medicine Approach to the Rescue of Function on Malignant Calmodulinopathic Long-QT Syndrome
PublisherLippincott Williams and Wilkins
MetadataShow full item record
AbstractRationale: 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 Ca 2+ /calmodulin (CaM)-dependent inactivation of L-type Ca 2+ 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 Ca 2+ cycling properties, and (3) diminished Ca 2+ /CaM-dependent inactivation of L-type Ca 2+ 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 Ca 2+ /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. Copyright 2016 American Heart Association, Inc.
SponsorsThis study was supported by American Heart Association Predoctoral Fellowship (W.B. Limpitikul), R01MH065531 (W.B. Limpitikul and I.E. Dick), The Magic that Matters Fund (D. DiSilvestre and G.F. Tomaselli), The Zegar Family Foundation (D. DiSilvestre and G.F. Tomaselli), and Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (M.J. Ackerman).
induced pluripotent stem cells
L-type calcium channels
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84994193768&doi=10.1161%2fCIRCRESAHA.116.309283&partnerID=40&md5=68183e7e993ecf83c6227c3b078960a7; http://hdl.handle.net/10713/9898