Heart failure gene therapy: the path to clinical practice

Abstract

Gene therapy, aimed at the correction of key pathologies being out of reach for conventional drugs, bears the potential to alter the treatment of cardiovascular diseases radically and thereby of heart failure. Heart failure gene therapy refers to a therapeutic system of targeted drug delivery to the heart that uses formulations of DNA and RNA, whose products determine the therapeutic classification through their biological actions. Among resident cardiac cells, cardiomyocytes have been the therapeutic target of numerous attempts to regenerate systolic and diastolic performance, to reverse remodeling and restore electric stability and metabolism. Although the concept to intervene directly within the genetic and molecular foundation of cardiac cells is simple and elegant, the path to clinical reality has been arduous because of the challenge on delivery technologies and vectors, expression regulation, and complex mechanisms of action of therapeutic gene products. Nonetheless, since the first demonstration of in vivo gene transfer into myocardium, there have been a series of advancements that have driven the evolution of heart failure gene therapy from an experimental tool to the threshold of becoming a viable clinical option. The objective of this review is to discuss the current state of the art in the field and point out inevitable innovations on which the future evolution of heart failure gene therapy into an effective and safe clinical treatment relies.

Keywords: cardiac; clinical translation; gene therapy; heart failure.

Figure 1.. Heart failure (HF) gene therapy concept:

HF gene therapy utilizes viral vectors such as adeno-associated vectors (AAV) (1) to deliver therapeutic DNA and RNA to nuclei of dysfunctional cardiomyocytes (2) to directly intervene within the genetic and molecular foundation of the cells. Myocardial infarction is shown as a common origin for HF development. Ultimate aim is targeted correction of key molecular defects being out of reach for conventional drugs utilizing the cells own transcriptional and translational machinery (3). Figure adapted from Davis et al. (Physiol Rev. 2008 Oct;88(4):1567–651).

Figure 2.. Vectors commonly used in cardiovascular gene transfer and specific characteristics:

To date, naked plasmid DNA, adeno-associated viruses (AAV) and adenovirus are used in 18.2%, 5.2% and 23% of 1.902 registered gene therapy clinical trials (see www.abedia.com/wiley/vectors.ph for continous update).

Figure 3.. Adeno-associated virus (AAV) genomic elemens and nuclear entry:

(A) Structure and regulatory elements of wild type (wtAAV) and recombinant (rAAV) AAV. The wtAAV genome consists of rep (green), cap (yellow) and internal repeat (ITR, white) elements. Exchange of rep/cap elements against therapeutic cargo (i.e. expression element; blue, and therapeutic DNA/RNA) the rAAV backbone with preserved ITRs. (B) AAVs enter target cells via receptor binding entailing endocytosis (1). Once inside the cell, endosomal AAV escapes into the cytoplasm (2) and enters the nucleus via nuclear pore complexes (3). Nuclear import and capsid disassembly (4) is followed by release of AAV single strand DNA payload and double strand synthesis (5), which entails synthesis of the therapeutic protein/peptide (6).

Figure 4.. Clinically applicable catheter-based cardiac-targeted gene delivery modes:

Antegrade intracorory perfusion (A) is currently used in phase I and phase II clinical HF gene therapy trials. Other forms (B-E) have successfully utilized in pre-clinical studies either being clinical routine or readily clinically applicable. Images modified from Tileman et al. (2012) Circ Res: 111

Figure 5.. Cardiac-biased controllable gene expression systems:

Transcriptional control using a cardiomyocyte-biased controllable gene expression system (1). In the absence of the oral ligand (“OFF-state”), the cardiomyocyte-specifically expressed ligand receptor (blue) and activator domain (orange) exist in an inactive conformation and transcription is kept off (2). Ingestion of the oral ligand leads to the “ON” State: in the presence of ligand (red), the two proteins (LR and AD) stably dimerize. The complex in an active conformation binds to the response element of the co-delivered therapeutic gene and transcription is turned on.

Figure 6.. Translational strategy for pre-clinical HF gene therapy development:

Integrative pipeline for pre-clinical development of HF and other cardiovascular gene therapy. For successful clinical implementation, experimental therapeutic proof-of-concept and molecular profile is ideally determined in molecular and small animal models (Basic Science). Human-relevant large animal disease models are key for translation towards use in humans enabling development and testing of clinically applicable delivery technology and target efficiency and safety. Date gleaned from this stage are essential for investigational drug status application and transition to clinical safety and exploratory dosing (phase I/II) trials in humans. Efficacy assessment (phase III) concludes successful clinical translation. Image modified with permission from J. Ritterhoff and P. Most (2012) Gene Therapy: 19.

Figure 7.. Overview of selected inotropic targets for HF gene therapy:

see section 6 for detailed mechanistic information. (Illustration Credit: Ben Smith).