You can’t unring a bell

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Science Translational Medicine  18 Mar 2015:
Vol. 7, Issue 279, pp. 279ec46
DOI: 10.1126/scitranslmed.aaa9870

More than half a million Americans have hypertrophic cardiomyopathy, a genetic disorder that causes heart muscle thickening and can lead to heart failure and sudden cardiac arrest. Hypertrophic cardiomyopathy results from a variety of possible mutations that cause overexpression of proteins involved in heart muscle contraction. The disease is transmitted in an autosomal dominant fashion, and current treatments consist of watchful waiting or attempts at symptom relief. It is not surprising that various strategies to arrest disease progression are under investigation, ranging from medications to exercise programs to gene suppression therapy.

Cannon et al. investigated the developmental stages at which gene suppression can prevent development of the hypertrophic cardiomyopathy phenotype. They used a murine transgenic model, in which two mutated copies of a gene causing hypertrophic cardiomyopathy were introduced, along with a regulator domain that allowed doxycycline to turn off this abnormal transgene. The authors tested turning off the transgene during three time periods: 0 to 6 weeks, 6 to 40 weeks, and 20 to 40 weeks of age. Only suppression of gene activity from 0 to 6 weeks prevented the development of the hypertrophic cardiomyopathy phenotype.

There are inherent limitations to murine models of human disease, and prior work has shown possible benefit from medication therapy started later in the disease process. Nonetheless, the work by Cannon et al. strongly implies that any gene suppression techniques must take developmental stage into account. It is possible that the ideal treatment may depend on whether the disease is diagnosed prior to the pubertal acceleration of hypertrophy, with gene suppression reserved for pre-pubertal children and medication therapy for adolescents and adults. Regardless, understanding the potential for irreversible induction of hypertrophy will allow for more nuanced research designs that will maximize the chance of detecting beneficial effects.

L. Cannon et al., Irreversible triggers for hypertrophic cardiomyopathy are established in the early postnatal period. J. Am. Coll. Cardiol. 65, 560–569 (2015). [Abstract]

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