ArticleHuman gene therapy2011
Cardiac gene transfer of short hairpin RNA directed against phospholamban effectively knocks down gene expression but causes cellular toxicity in canines.
Article in Human gene therapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
32 citing papers in PubMed, 52 citations in OpenAlex.
- Gene Therapy for Heart Failure: Impact on Mitochondrial Dysfunction.Biomedicines · 2026Review
- Small RNA or oligonucleotide drugs and challenges in evaluating drug-drug interactions.Frontiers in pharmacology · 2025Review
- SERCA2a overexpression improves muscle function in a canine Duchenne muscular dystrophy model.Molecular therapy. Methods & clinical development · 2024Article
- Review
- Harnessing Intronic microRNA Structures to Improve Tolerance and Expression of shRNAs in Animal Cells.Methods and protocols · 2022Article
- Efficient and Precise Processing of the Optimized Primary Artificial MicroRNA in a Huntingtin-Lowering Adeno-Associated Viral Gene TherapyHuman gene therapy · 2022Article
- RISC-y Business: Limitations of Short Hairpin RNA-Mediated Gene Silencing in the Brain and a Discussion of CRISPR/Cas-Based Alternatives.Frontiers in molecular neuroscience · 2022Review
- MicroRNA-Related Strategies to Improve Cardiac Function in Heart Failure.Frontiers in cardiovascular medicine · 2021Review
- Endogenous MicroRNA Competition as a Mechanism of shRNA-Induced Cardiotoxicity.Molecular therapy. Nucleic acids · 2020Article
- Viral expression of a SERCA2a-activating PLB mutant improves calcium cycling and synchronicity in dilated cardiomyopathic hiPSC-CMs.Journal of molecular and cellular cardiology · 2020Article
- Translation of MicroRNA-Based Huntingtin-Lowering Therapies from Preclinical Studies to the Clinic.Molecular therapy : the journal of the American Society of Gene Therapy · 2018Review
- Use of Adeno-Associated Virus Vector for Cardiac Gene Delivery in Large-Animal Surgical Models of Heart Failure.Human gene therapy. Clinical development · 2017Review
- Safe and Efficient Silencing with a Pol II, but Not a Pol lII, Promoter Expressing an Artificial miRNA Targeting Human Huntingtin.Molecular therapy. Nucleic acids · 2017Article
- Cardiac gene therapy with adeno-associated virus-based vectors.Current opinion in cardiology · 2017Article
- Design, Characterization, and Lead Selection of Therapeutic miRNAs Targeting Huntingtin for Development of Gene Therapy for Huntington's Disease.Molecular therapy. Nucleic acids · 2016Article
- Rheostatic Regulation of the SERCA/Phospholamban Membrane Protein Complex Using Non-Coding RNA and Single-Stranded DNA oligonucleotides.Scientific reports · 2015Article
- Altered myocardial calcium cycling and energetics in heart failure--a rational approach for disease treatment.Cell metabolism · 2015Review
- Recombinant AAV as a platform for translating the therapeutic potential of RNA interference.Molecular therapy : the journal of the American Society of Gene Therapy · 2014Review
- A titratable two-step transcriptional amplification strategy for targeted gene therapy based on ligand-induced intramolecular folding of a mutant human estrogen receptor.Molecular imaging and biology · 2014Article
- The potential of adeno-associated viral vectors for gene delivery to muscle tissue.Expert opinion on drug delivery · 2014Review
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
Derangements in calcium cycling have been described in failing hearts, and preclinical studies have suggested that therapies aimed at correcting this defect can lead to improvements in cardiac function and survival. One strategy to improve calcium cycling would be to inhibit phospholamban (PLB), the negative regulator of SERCA2a that is upregulated in failing hearts. The goal of this study was to evaluate the safety and efficacy of using adeno-associated virus (AAV)-mediated cardiac gene transfer of short hairpin RNA (shRNA) to knock down expression of PLB. Six dogs were treated with self-complementary AAV serotype 6 (scAAV6) expressing shRNA against PLB. Three control dogs were treated with empty AAV6 capsid, and two control dogs were treated with scAAV6 expressing dominant negative PLB. Vector was delivered via a percutaneously inserted cardiac injection catheter. PLB mRNA and protein expression were analyzed in three of six shRNA dogs between days 16 and 26. The other three shRNA dogs and five control dogs were monitored long-term to assess cardiac safety. PLB mRNA was reduced 16-fold, and PLB protein was reduced 5-fold, with treatment. Serum troponin elevation and depressed cardiac function were observed in the shRNA group only at 4 weeks. An enzyme-linked immunospot assay failed to detect any T cells reactive to AAV6 capsid in peripheral blood mononuclear cells, heart, or spleen. Microarray analysis revealed alterations in cardiac expression of several microRNAs with shRNA treatment. AAV6-mediated cardiac gene transfer of shRNA effectively knocks down PLB expression but is associated with severe cardiac toxicity. Toxicity may result from dysregulation of endogenous microRNA pathways.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.