ArticleMolecular therapy. Nucleic acids2019
Optimizing Synthetic miRNA Minigene Architecture for Efficient miRNA Hairpin Concatenation and Multi-target Gene Knockdown.
Article in Molecular therapy. Nucleic acids, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 16 citations in OpenAlex.
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- Arylsulfatases and neuraminidases modulate engagement of CCR5 by chemokines by removing key electrostatic interactions.Scientific reports · 2024Article
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- Genetic knockout ofFrontiers in cellular neuroscience · 2023Article
- Adipose-derived stem cell spheroids are superior to single-cell suspensions to improve fat autograft long-term survival.Journal of cellular and molecular medicine · 2022Article
- Development andFrontiers in neurology · 2022Article
- NADPH Oxidase 3 Deficiency Protects From Noise-Induced Sensorineural Hearing Loss.Frontiers in cell and developmental biology · 2022Article
- Preclinical Experimental Applications of miRNA Loaded BMSC Extracellular Vesicles.Stem cell reviews and reports · 2021Review
- Redox activation of excitatory pathways in auditory neurons as mechanism of age-related hearing loss.Redox biology · 2020Article
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Synthetic microRNA (miRNA) minigenes (SMIGs) have a major potential for molecular therapy; however, their optimal architecture still needs to be determined. We have previously optimized the stem structure of miRNA hairpins for efficient gene knockdown. Here, we investigate the overall architecture of SMIGs driven by polymerase II-dependent promoters. When miRNA hairpins were placed directly behind the promoter, gene knockdown was inefficient as compared with constructs containing an intercalated sequence ("spacer"). Spacer sequence was relevant for knockdown efficiency and concatenation potential: GFP-based sequences (even when truncated or including stop codons) were particularly efficient. In contrast, a spacer of similar length based on a CD4 intronic sequence was entirely inefficient. Spacer sequences influenced miRNA steady-state levels without affecting transcript stability. We demonstrate that with an optimized spacer, up to five concatenated hairpins targeting two different genes are efficiently expressed and able to knock down their respective targets. Transplantation of hematopoietic stem cells containing a CCR5 knockdown SMIG demonstrated a sustained in vivo efficacy of our approach. In summary, we have defined features that optimize SMIG efficiency. Based on these results, optimized knockdown of genes of interest, such as the HIV co-receptor CCR5 and the NADPH oxidase subunit p22
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