Protein engineering and gene therapy to control heart beat

Protein engineering and gene therapy to control heart beat

There is a dire need to be able to modulate cardiac contraction to better manage cardiovascular disease. For example, a majority of cardiomyopathies present with impaired contraction. Many strategies to improve cardiac contraction (positive inotropes) do so by increasing the signal for contraction (that is, intracellular Ca2+). Owing to the universal nature of Ca2+ signalling, increasing Ca2+ not only enhances contraction, but also leads to a variety of negative side effects (arrhythmias and cell death) that ultimately increases mortality.

The amount of Ca2+ bound to Troponin C (TnC), the Ca2+-dependent switch in the heart, is a primary determinant of the strength of cardiac contraction. Hence, modulating contraction through TnC has been an enticing pharmaceutical goal for many decades.

Unfortunately, there are no specific therapeutics that modulate TnC without affecting other systems (for example, phosphodiesterases and hypotension). A promising strategy to solely modulate the Ca2+sensitivity of TnC is through rationally customizing Ca2+ binding to TnC. By applying the principles that govern Ca2+ binding to TnC, authors have smartly formulated TnC variants with a wide range of Ca2+ sensitivities.

These variants effectively modulate Ca2+ sensitivity and force development from in silico to in vitro. Whether TnC engineering can translate in vivo to modulate cardiac function with molecular precision is currently unknown.

Authors show that our rationally customized TnC can improve function and performance in a common heart pathology–myocardial infarction (MI). They find that the Ca2+-sensitizing TnC L48Q expressed before an MI, enhances heart function and performance without any adverse effects (that is, slow relaxation, arrhythmias or changing Ca2+).

Moreover, expression of TnC L48Q after the MI therapeutically enhances cardiac function and performance, without compromising survival. Thus, smartly formulating TnC combined with gene therapy is a powerful tool to develop unique and novel therapies with molecular precision to combat heart disease.