Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure

Abstract

BACKGROUND Increased protein phosphatase-1 (PP1) in heart failure (HF) induces molecular changes deleterious to the cardiac cell. Inhibiting PP1 through the overexpression of a constitutively active inhibitor-1 (I-1c) has been shown to reverse cardiac dysfunction in a model of ischemic HF. OBJECTIVES We sought to determine the therapeutic efficacy of a re-engineered adeno-associated viral vector carrying I-1c (BNP116.I-1c) in a preclinical model of nonischemic HF, and to assess thoroughly the safety of BNP116.I-1c gene therapy. METHODS Volume-overload HF was created in Yorkshire swine by inducing severe mitral regurgitation (MR). One month after MR induction, pigs were randomized to intracoronary delivery of either BNP116.I-1c (n = 6) or saline (n = 7). Therapeutic efficacy and safety were evaluated 2 months after gene delivery. Additionally, 24 naïve pigs received different doses of BNP116.I-1c for safety evaluation. RESULTS At 1 month after MR induction, pigs developed HF as evidenced by increased left ventricular (LV) end-diastolic pressure and LV volume indexes. Treatment with BNP116.I-1c resulted in improved LV ejection fraction (−5.9 ± 4.2% vs. 5.5 ± 4.0%; p < 0.001) and adjusted dP/dt maximum (−3.39 ± 2.44 s-1 vs. 1.30 ± 2.39s-1; p = 0.007). Moreover, BNP116.I-1c-treated pigs also exhibited a significant increase in left atrial (LA) ejection fraction at 2 months after gene delivery (−4.3 ± 3.1% vs. 7.5 ± 3.1%; p = 0.02). In vitro I-1c gene transfer in isolated LA myocytes from both pigs and rats exhibited increased calcium transient amplitude, consistent with its positive impact on LA contraction. We found no evidence of adverse electrical remodeling, arrhythmogenicity, activation of a cellular immune response, or off-target organ damage by BNP116.I-1c gene therapy in pigs. CONCLUSIONS Intracoronary delivery of BNP116.I-1c was safe and improved contractility of the left ventricle and atrium in a large animal model of nonischemic HF.

Human Cardiac Gene Therapy

“…Given the enormous clinical need for the development of improved treatment options of both inherited and acquired cardiovascular diseases, it is not surprising that extensive preclinical research has been performed to test AAV vectors to treat cardiovascular diseases, most prominently heart failure. These intense efforts resulted in a plethora of successful studies, especially in rodents 47–50 , but also in pre-clinically relevant large animal models 51–55 Based on extensive pre-clinical studies focused on delivering the cardiac isoform of the sarcoplasmic reticulum calcium ATPase pump, a dose escalating First in Man clinical study was initiated in patients with severe heart failure 56 . Phase 1 of the CUPID trial demonstrated the safety of delivering an AAV1 vector encoding SERCA2a via antegrade intracoronary infusion and indicated potential clinical benefit at a dose of 10 13 vg 57, 58 .…”

Congestive Heart Failure: Current Treatment and Therapies under Realm of Research

“…The results demonstrated in the animal model that the gene therapy was safe and significantly reversed heart failure by 25 percent in the left ventricle and by 20 percent in the left atrium. The treatment group also showed a ten percent decrease in heart enlargement, a common symptom of heart disease [29]. Carfostin will soon undergo clinical trials.…”

An automated hybrid bioelectronic system for autogenous restoration of sinus rhythm in atrial fibrillation

“…Although additional research would be required for such translation, it is important to note that epicardial access and interventions by minimally invasive thoracoscopic surgery or a subxiphoidal approach are already feasible and safe, and device implantation for cardiac rhythm management is currently one of the mainstays of treatment. In addition, recent clinical trials have demonstrated that human cardiac gene therapy is feasible and safe (43)(44)(45), and new human cardiac gene therapeutic studies are being planned (46).…”