Gene Therapies—Protein Augmentation or RNAi-mediated Depletion
Principles of Gene Therapies
The term 'gene therapy' in general refers to the therapeutic delivery of a nucleic acid sequence to diseased organs or tissues of patients as a drug, further defined by the regulatory term Gene Therapy Medicinal Product (GTMP). Originating from experimental gene supplementation strategies for the therapeutic in vivo restoration of a missing or down-regulated protein with pathophysiological relevance, such as in monogenic or acquired diseases, the therapeutic modalities were recently expanded by gene silencing and gene editing technologies. Accordingly, gene supplementation is being developed for homozygous familial hypercholesterolaemia (FH), where the LDL receptor (LDLR) is missing, and this is currently investigated in a phase 1/2a first-in-man clinical trial (NCT02651675). Employing recombinant adeno-associated virus (rAAV)-based liver-directed human LDLR gene therapy as GTMP, LDL-C levels will be used as surrogate biomarker for LDLR expression.[173–175]
GTMPs for the treatment of cardiomyopathies (CMPs), heart failure, and peripheral arterial disease (PAD) have been described in recent reviews.[173–175] They are predicating on viral-based gene supplementation therapies and have also reached early clinical studies.[173–175] While clinical development of adenovirus type 5 (Ad5)-based human adenylyl cyclase 6 (Ad5-hAC6) treatment of patients with heart failure with reduced ejection fraction (HFrEF) awaits beginning of the FLOURISH (phase 3) trial (NCT03360448) via a single one-time intracoronary administration, the CUPID (Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease) trial series using rAAV1-SERCA2a-based treatment of HFrEF and dilated cardiomyopathy applying the same invasive mode of administration was ended prematurely at stage phase 2b (NCT01643330) due to insufficient myocardial SERCA2a gene delivery.
Gene Therapies Targeting Non-cardiac Monogenic Diseases
The U.S. Food and Drug Administration (FDA) approved rAAV-based GTMPs Luxturna and Zolgensma, treating hereditary retinal and spinal muscular dystrophy by replacing a defective RPE65 and SMN1 gene in retinal pigment epithelium and motor-neurons, respectively, mark the long-sought clinical breakthrough for gene therapy. Although the therapeutic payload should be smaller than 4.4 Kb, there is a robust pipeline of rAAV-based GTMPs for various orphan indications ranging from hereditary bleeding (e.g. hemophilia A/B) and neurological disorders (e.g. Huntington disease) to muscular (Pompe disease) and lysosomal storage (MPS I and II) diseases, amongst others. Although the natural barriers impeding the transfer efficacy of rAAVs are grossly different between target organs,[176–178] they were mastered in aforementioned indications, e.g. by intraocular or intrathecally injections of rAAV2-RPE65 and rAAV9-SNM1, respectively. Other indications, such as liver diseases, can be addressed by systemic injections and sufficient hepatic transduction via the rAAV serotypes 8 and or 5,[179–187] given the organ's natural function of clearing and detoxifying the bloodstream. Given the field's current momentum and emerging regulatory paths, the FDA is expecting 5–10 new GTMP approvals per year by 2025.
Gene Therapy for Cardiomyopathies and Heart Failure
The heart proved as a difficult target organ for rAAV vectors which yet impedes the development of clinically efficient cardiac-directed gene therapy protocols that are still based on percutaneous catheter-based administration into coronary arteries or veins.[159,189] Although sufficient myocardial gene delivery by these routes has been achieved in small and large animal models with therapeutic success regarding improved cardiac function[190–200] clinical trials, such as CUPID, employing this type of invasive administration failed to demonstrate clinical efficacy for rAAV1-SERCA2a.[159,162,201] The advent of directed rAAV evolution technologies to engineer synthetic cardiac-specific rAAVs that are amenable to simple systemic intravenous administration and transduce the heart with highest precision and minimal off-target activity is key to gain therapeutic access to the heart. As such, it may be advisable to delay clinical development of other validated heart failure targets such as S100A1 or the GRK2 inhibitor bARKct until simple and efficient delivery tools are at hand that may enable development of next-generation cardiac GTMPs with sufficient myocardial transduction efficiency for gene supplementation, gene silencing, and gene-editing strategies to treat the various forms of acquired heart failure as well as hereditary cardiomyopathies[165,202–204] with improved clinical delivery systems.[159,162,201,205–209] Nevertheless, it will be of equal importance to understand whether Ad5 may be a suitable carrier for cardiac indications such as heart failure against current mainstream scientific opinion given previous results from Ad5-hAC6 clinical development. Figure 6 illustrates currently employed tools for in vivo myocardial gene or RNAi therapy.
Gene therapy for protein augmentation or RNAi-mediated depletion. The 'classical' approach of gene transfer for protein augmentation or (in the case of monogenic disorders) protein substitution recently gained clinical impact in the hemophilia field where the missing coagulation factor genes could be successfully and durably transferred to the liver using AAV vectors. In the cardiovascular field, cardiac-targeted gene augmentation (SERCA2a) or ablation (phospholamban) therapies were successful in animal models, but this could not yet be translated to the clinical arena due to still insufficient gene transfer efficacy in patients.
Eur Heart J. 2020;41(40):3884-3899. © 2020 Oxford University Press
Copyright 2007 European Society of Cardiology. Published by Oxford University Press. All rights reserved.