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)
Text
271888.pdf - Published Version Available under License Creative Commons Attribution. 2MB |
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 |
University Staff: Request a correction | Enlighten Editors: Update this record