Journal
MOLECULAR THERAPY
Volume 23, Issue 1, Pages 43-52Publisher
CELL PRESS
DOI: 10.1038/mt.2014.178
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Funding
- EU FP7 (PERSIST) [222878]
- AFM
- FWO
- EHA
- Geconcerteerde Onderzoeksactie (GOA) (EPIGEN, VUB)
- STK
- Willy Gepts Fund (VUB)
- VUB Strategic Research Program Groeier
- VUB Industrieel Onderzoeksfonds (Groups of Expertise in Applied Research (GEAR))
- VUB Proof of Concept Grant (Industrieel Onderzoeksfonds)
- Belgian State
- Nationaal Kankerplan
- Vlaamse Liga tegen Kanker
- Vlaamse Stichting tegen Kanker
- Fundacion Cardiovascular de Colombia/Colciencias Fellowship
- AFM PhD Fellowship
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Gene therapy is a promising emerging therapeutic modality for the treatment of cardiovascular diseases and hereditary diseases that afflict the heart. Hence, there is a need to develop robust cardiac-specific expression modules that allow for stable expression of the gene of interest in cardiomyocytes. We therefore explored a new approach based on a genome-wide bioinformatics strategy that revealed novel cardiac-specific cis-acting regulatory modules (CS-CRMs). These transcriptional modules contained evolutionary-conserved clusters of putative transcription factor binding sites that correspond to a molecular signature associated with robust gene expression in the heart. We then validated these CS-CRMs in vivo using an adeno-associated viral vector serotype 9 that drives a reporter gene from a quintessential cardiac-specific a-myosin heavy chain promoter. Most de novo designed CS-CRMs resulted in a > 10-fold increase in cardiac gene - expression. The most robust CRMs enhanced cardiac-specific transcription 70- to 100-fold. Expression was sustained and restricted to cardiomyocytes. We then combined the most potent CS-CRM4 with a synthetic heart and muscle-specific promoter (SPc5-12) and obtained a significant 20-fold increase in cardiac gene expression compared to the cytomegalovirus promoter. This study underscores the potential of rational vector design to improve the robustness of cardiac gene therapy.
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