Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure

Abstract

Importance Gene transfer has rarely been tested in randomized clinical trials. Objective To evaluate the safety and efficacy of intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) in heart failure. Design, Setting, and Participants A randomized, double-blind, placebo-controlled, phase 2 clinical trial was conducted in US medical centers (randomization occurred from July 19, 2010, to October 30, 2014). Participants 18 to 80 years with symptomatic heart failure (ischemic and nonischemic) and an ejection fraction (EF) of 40% or less were screened; 86 individuals were enrolled, and 56 were randomized. Data analysis was of the intention-to-treat population. Participants underwent exercise testing and measurement of left ventricular EF (echocardiography) and then cardiac catheterization, where left ventricular pressure development (+dP/dt)and decline (−dP/dt) were recorded. Participants were randomized (3:1 ratio) to receive 1 of 5 doses of intracoronary Ad5.hAC6 or placebo. Participants underwent a second catheterization 4 weeks later for measurement of dP/dt. Exercise testing and EF were assessed 4 and 12 weeks after randomization. Interventions Intracoronary administration of Ad5.hAC6 (3.2 × 109 to 1012 virus particles) or placebo. Main Outcomes and Measures Primary end points included exercise duration and EF before and 4 and 12 weeks after randomization and peak rates of +dP/dt and −dP/dt before and 4 weeks after randomization. Fourteen placebo participants were compared (intention to treat) with 24 Ad5.hAC6 participants receiving the highest 2 doses (D4 + 5). Results Fifty-six individuals were randomized and monitored for up to 1 year. Forty-two participants (75%) received Ad5.hAC6 (mean [SE] age, 63 [1] years; EF, 30% [1%]), and 14 individuals (25%) received placebo (age, 62 [1] years; EF, 30% [2%]). Exercise duration showed no significant group differences (4 weeks, P = .27; 12 weeks, P = .47, respectively). The D4 + 5 participants had increased EF at 4 weeks (+6.0 [1.7] EF units; n = 21; P < .004), but not 12 weeks (+3.0 [2.4] EF units; n = 21; P= .16). Placebo participants showed no increase in EF at 4 weeks or 12 weeks. Exercise duration showed no between-group differences (4-week change from baseline: placebo, 27 [36] seconds; D4 + 5, 44 [25] seconds; P = .27; 12-week change from baseline: placebo, 44 [28] seconds; D4 + 5, 58 [29 seconds, P = .47). AC6 gene transfer increased basal left ventricular peak −dP/dt (4-week change from baseline: placebo, +93 [51] mm Hg/s; D4 + 5, -39 [33] mm Hg/s; placebo [n = 21]; P < .03); AC6 did not increase arrhythmias. The admission rate for patients with heart failure was 9.5% (4 of 42) in the AC6 group and 28.6% (4 of 14) in the placebo group (relative risk, 0.33 [95% CI, 0.08-1.36]; P = .10). Conclusions and Relevance AC6 gene transfer safely increased LV function beyond standard heart failure therapy, attainable with one-time administration. Larger trials are warranted. Trial Registration clinicaltrials.gov Identifier: NCT007870...

Hypoxia-responsive zinc finger E-box-binding homeobox 2 (ZEB2) regulates a network of calcium-handling genes in the injured heart

“… 75 Thus, the beneficial outcomes of ADCY6 in preclinical studies are promising and are currently under investigation in clinical trials on HF patients. 47 , 76 , 77 In the current study, we observed an increase in phosphorylation of PLN in Zeb2-overexpressing hearts, indicating a relieve of its inhibitory effect on the Ca 2+ pump SERCA2a, and consequently an increased Ca 2+ uptake in the SR ( Figure 3 ). Additionally, we observed that cardiomyocytes isolated from Zeb2 cTg mice post-IR displayed an increase in Ca 2+ transient amplitude and a shorter decay time at higher frequencies, further supporting an improved Ca 2+ reuptake in those cells ( Figure 5 ).…”

“…We observed that the expression of various genes related to cardiomyocyte contractility is reduced upon ischaemic injury (see Supplementary material online , Figure S4A ), which correlates with a decline in cardiac function. 47–51 This decrease was restored upon ZEB2 overexpression in the ischaemic heart (see Supplementary material online , Figure S4B ), suggesting a ZEB2-mediated rescue of contractility-related genes after ischaemic injury.…”

The Role of Cyclic AMP Signaling in Cardiac Fibrosis

“…In particular, overexpression of AC6 in cardiac fibroblasts decreased collagen formation, myofibroblast transdifferentiation, and the expression of the pro-fibrotic genes induced by TGFβ [13]. In line with these results, a phase 2 clinical trial during which intracoronary gene transfer of AC6 was performed in heart failure patients highlighted clear beneficial effects of AC6 gene transfer on left ventricular function [81]. On the other hand, AC5 appears to contribute to aging-induced cardiomyopathy, as well as heart remodeling and dysfunction induced by chronic catecholamine stress or pressure-overload.…”

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

“…Results from this placebo-controlled, randomized clinical trial of 56 HFrEF patients confirmed the safety of Ad5.hAC6 [clinicaltrials.gov Identifier NCT00787059] (Hammond et al, 2016). Furthermore, patients receiving the two highest doses (out of five possible different doses) of Ad5.hAC6 showed an acute improvement in EF, assessed 4 weeks post-viral delivery (Hammond et al, 2016). The promising results from this Phase II clinical trial paved the way for the 'FLOURISH' trial, a Phase III follow-up [clinicaltrials.gov Identifier NCT03360448] (Penny et al, 2018).…”