Correcting Calcium Dysregulation in Chronic Heart Failure Using SERCA2a Gene Therapy

Abstract

Chronic heart failure (CHF) is a major contributor to cardiovascular disease and is the leading cause of hospitalization for those over the age of 65, which is estimated to account for close to seventy billion dollars in healthcare costs by 2030 in the US alone. The successful therapies for preventing and reversing CHF progression are urgently required. One strategy under active investigation is to restore dysregulated myocardial calcium (Ca2+), a hallmark of CHF. It is well established that intracellular Ca2+ concentrations are tightly regulated to control efficient myocardial systolic contraction and diastolic relaxation. Among the many cell surface proteins and intracellular organelles that act as the warp and woof of the regulatory network controlling intracellular Ca2+ signals in cardiomyocytes, sarco/endoplasmic reticulum Ca2+ ATPase type 2a (SERCA2a) undoubtedly plays a central role. SERCA2a is responsible for sequestrating cytosolic Ca2+ back into the sarcoplasmic reticulum during diastole, allowing for efficient uncoupling of actin-myosin and subsequent ventricular relaxation. Accumulating evidence has demonstrated that the expression of SERCA2a is downregulated in CHF, which subsequently contributes to severe systolic and diastolic dysfunction. Therefore, restoring SERCA2a expression and improving cardiomyocyte Ca2+ handling provides an excellent alternative to currently used transplantation and mechanical assist devices in the treatment of CHF. Indeed, advancements in safe and effective gene delivery techniques have led to the emergence of SERCA2a gene therapy as a potential therapeutic choice for CHF patients. This mini-review will succinctly detail the progression of SERCA2a gene therapy from its inception in plasmid and animal models, to its clinical trials in CHF patients, highlighting potential avenues for future work along the way.

Nkx2.5 insufficiency leads to atrial electrical remodeling through Wnt signaling in HL‑1 cells

“…SERCA2a is responsible for pumping calcium back to the SR during diastole to avoid an increase in intracytoplasmic calcium concentration, which may increase the sodium-calcium exchange and triggered activity. PLB has been demonstrated to bind to SERCA2a and inhibit its activity; following phosphorylation, this inhibition of SERCA2a is lost (17). In the present study, SECA2a and P-PLB expression was impaired during Nkx2.5 silencing.…”

Potential roles of mediator Complex Subunit 13 in Cardiac Diseases

“…TH also positively regulates sarcoplasmic reticulum Ca 2+ ATPase ( Serca2a ) gene expression 69 , 76 , 77 ( Figure 3 ). Serca2a is an important Ca 2+ pump for the maintenance of Ca 2+ homeostasis, which is associated with myocardial calcium handling and plays a critical role in maintaining cardiac function 78 , 79 .…”

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

“…The results of the initial Phase I and IIa trials suggested that AAV1.SERCA2a treatment reduced the number of cardiac events in HF patients ( Jaski et al, 2009 ; Jessup et al, 2011 ); however, larger Phase IIb clinical trials failed to show improvement in any primary or secondary endpoints, leading to their early termination ( Hulot et al, 2017 ). The failure of these clinical trials suggests the dosage and delivery method of AAV1.SERCA2a may require optimizing ( Hulot et al, 2016 ) [SERCA2a gene therapy in HF has been extensively reviewed elsewhere ( Samuel et al, 2018 )]. Despite the lack of promising results for AAV1.SERCA2a, clinical trials are underway for istaroxime, a dual functional luso-inotropic agent which both stimulates SERCA2a and inhibits Na + /K + ATPase ( Micheletti et al, 2002 ) ( Figure 4 and Table 2 ).…”