Adenoviral vectors for cardiovascular gene therapy applications: a clinical and industry perspective

Schwartze, J. T., Havenga, M., Bakker, W. A. M., Bradshaw, A. C. and Nicklin, S. A. (2022) Adenoviral vectors for cardiovascular gene therapy applications: a clinical and industry perspective. Journal of Molecular Medicine, 100(6), pp. 875-901. (doi: 10.1007/s00109-022-02208-0) (PMID:35606652) (PMCID:PMC9126699)

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Abstract

Despite the development of novel pharmacological treatments, cardiovascular disease morbidity and mortality remain high indicating an unmet clinical need. Viral gene therapy enables targeted delivery of therapeutic transgenes and represents an attractive platform for tackling acquired and inherited cardiovascular diseases in the future. Current cardiovascular gene therapy trials in humans mainly focus on improving cardiac angiogenesis and function. Encouragingly, local delivery of therapeutic transgenes utilising first-generation human adenovirus serotype (HAd)-5 is safe in the short term and has shown some efficacy in drug refractory angina pectoris and heart failure with reduced ejection fraction. Despite this success, systemic delivery of therapeutic HAd-5 vectors targeting cardiovascular tissues and internal organs is limited by negligible gene transfer to target cells, elimination by the immune system, liver sequestration, off-target effects, and episomal degradation. To circumvent these barriers, cardiovascular gene therapy research has focused on determining the safety and efficacy of rare alternative serotypes and/or genetically engineered adenoviral capsid protein-modified vectors following local or systemic delivery. Pre-clinical studies have identified several vectors including HAd-11, HAd-35, and HAd-20–42-42 as promising platforms for local and systemic targeting of vascular endothelial and smooth muscle cells. In the past, clinical gene therapy trials were often restricted by limited scale-up capabilities of gene therapy medicinal products (GTMPs) and lack of regulatory guidance. However, significant improvement of industrial GTMP scale-up and purification, development of novel producer cell lines, and issuing of GTMP regulatory guidance by national regulatory health agencies have addressed many of these challenges, creating a more robust framework for future adenoviral-based cardiovascular gene therapy. In addition, this has enabled the mass roll out of adenovirus vector-based COVID-19 vaccines.

Item Type:Articles
Additional Information:SAN is supported by the British Heart Foundation (Project Grant PG/17/17/32877 and Centre of Research Excellence Award RE/18/6/34217). ACB is supported by a Personal Research Fellowship from the Royal Society of Edinburgh.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Schwartze, Mr Julian and Bradshaw, Dr Angela
Authors: Schwartze, J. T., Havenga, M., Bakker, W. A. M., Bradshaw, A. C., and Nicklin, S. A.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Journal of Molecular Medicine
Publisher:Springer
ISSN:0946-2716
ISSN (Online):1432-1440
Published Online:24 May 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Journal of Molecular Medicine 100(6): 875-901
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
300489Cardiac gene therapy with angiotensin-(1-9): dissecting the underlying mechanism for preservation of cardiac function post-myocardial infarctionStuart NicklinBritish Heart Foundation (BHF)PG/17/17/32877CAMS - Cardiovascular Science
303944BHF Centre of ExcellenceColin BerryBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science