ArticleMolecular therapy : the journal of the American Society of Gene Therapy2015
Genome-wide computational analysis reveals cardiomyocyte-specific transcriptional Cis-regulatory motifs that enable efficient cardiac gene therapy.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
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- AAV Vector Toolkit for the Delivery and Expression of the Artificial microRNA in the Murine Heart.Biotech (Basel (Switzerland)) · 2026Article
- Identification of a robust promoter in mouse and human hepatocytes by in vivo biopanning of a barcoded AAV library.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Gene therapy for age-related macular degeneration: a promising frontier in vision preservation.Cell communication and signaling : CCS · 2025Review
- Prospective approaches to gene therapy computational modeling - spotlight on viral gene therapy.Journal of pharmacokinetics and pharmacodynamics · 2024Review
- Transcriptional Targeting Approaches in Cardiac Gene Transfer Using AAV Vectors.Pathogens (Basel, Switzerland) · 2023Review
- Evolution of molecular switches for regulation of transgene expression by clinically licensed gluconate.Nucleic acids research · 2023Article
- Prolonged control of insulin-dependent diabetes via intramuscular expression of plasmid-encoded single-strand insulin analogue.Genes & diseases · 2023Article
- Engineered bacterial voltage-gated sodium channel platform for cardiac gene therapy.Nature communications · 2022Article
- AAV Vector-Mediated Antibody Delivery (A-MAD) in the Central Nervous System.Frontiers in neurology · 2022Review
- Synthetic Biology: Emerging Concepts to Design and Advance Adeno-Associated Viral Vectors for Gene Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Review
- Deep Parallel Characterization of AAV Tropism and AAV-Mediated Transcriptional ChangesFrontiers in immunology · 2021Article
- Constructing and evaluating caspase-activatable adeno-associated virus vector for gene delivery to the injured heart.Journal of controlled release : official journal of the Controlled Release Society · 2020Article
- Variability in Cardiac miRNA-122 Level Determines Therapeutic Potential of miRNA-Regulated AAV Vectors.Molecular therapy. Methods & clinical development · 2020Article
- Engineering adeno-associated virus vectors for gene therapy.Nature reviews. Genetics · 2020Review
- Distinct transduction of muscle tissue in mice after systemic delivery of AAVpo1 vectors.Gene therapy · 2020Article
- Next-generation muscle-directed gene therapy by in silico vector design.Nature communications · 2019Article
- Enhancing atrial-specific gene expression using a calsequestrin cis-regulatory module 4 with a sarcolipin promoter.The journal of gene medicine · 2018Article
- A Calsequestrin Cis-Regulatory Motif Coupled to a Cardiac Troponin T Promoter Improves Cardiac Adeno-Associated Virus Serotype 9 Transduction Specificity.Human gene therapy · 2018Article
- Widespread transduction of astrocytes and neurons in the mouse central nervous system after systemic delivery of a self-complementary AAV-PHP.B vector.Gene therapy · 2018Article
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Authors and funding
13 authors.
Funding
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Abstract
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 α-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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