Development of MYBPC3-based gene therapy to regulate RYR2 activity

Project: Research


  • Fujian Lu (PI)


Proper regulation of Ca2+ is critical for cardiomyocyte function, growth, and survival. Heart muscle cells that are exposed to chronic excess workload or that harbor mutations in Ca2+ handling genes have abnormal Ca2+ handling, resulting in impaired heart muscle cell contraction or rhythm. To better understand Ca2+ regulation in heart muscle cells, we identified proteins that are located within their key Ca2+ handling units, known as dyads. Many identified proteins were previously known to be located in these structures, validating our technique. We were surprised to find that myosin binding protein C3 (MYBPC3), a component of the contractile machinery of heart muscle cells, was identified within dyads. We validated this finding and then studied its functional significance by determining if producing more MYBPC3 in heart muscle cells would alter dyad function. To do this, we studied mice engineered to contain a patient mutation in the gene RYR2, which causes excessive dyad Ca2+ release under conditions of high adrenaline, mimicking the human disease catecholaminergic polymorphic ventricular tachycardia (CPVT). Remarkably, we found that producing more MYBPC3 in heart muscle cells protected these CPVT mice from propensity for arrhythmia. These findings suggest that this discovery may be translated into novel approaches to treat cardiac arrhythmia and dysfunction caused by abnormal dyad function. In this proposal, we will (1) define the minimum fragment of MYBPC3 that is required to normalize pathological RYR2 activation in CPVT mice for gene therapy; and (2) determine the effect of MYBPC3 and truncating mutations on RYR2 post-translational modification and function. This work may ultimately lead to new treatments for CPVT and other more common conditions exacerbated by excessive RYR2 activity.
Award amount$131,356.00
Award date01/01/2020
Program typePostdoctoral Fellowship
Award ID20POST35200233
Effective start/end date01/01/202012/31/2021