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Published on: August 2, 2018
Dynamically covalent lipid nanoparticles mediate CRISPR-Cas9 genome editing against choroidal neovascularization in
Desheng Cao1, Junliang Zhu1, Yang Guo2
1Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China.
Abstract:
As an important modality for choroidal neovascularization (CNV) treatment, intravitreal injection of vascular endothelial growth factor A (VEGFA) inhibitors suffers from undesired response rate, low patient compliance, and ocular damage. Here, dynamically covalent lipid nanoparticles (LNPs) were engineered to mediate VEGFA gene editing and CNV treatment by codelivering Cas9 mRNA (mCas9) and single guide RNA (sgRNA) targeting VEGFA (sgVEGFA). A library of lipidoids bearing iminoboronate ester linkage was developed via facile "one-pot" synthesis, and the top-performing lipidoid-A4B3C7 was formulated into LNP-A4B3C7 with the highest mRNA transfection efficiency. Inside the diseased retinal pigment epithelial cells, LNPs were dissociated upon H2O2-triggered lipidoid degradation, facilitating mRNA/sgRNA release to potentiate the gene editing efficiency. In laser-induced CNV mice, mCas9/sgVEGFA@LNP-A4B3C7 after single intravitreal injection led to pronounced VEGFA disruption and CNV area reduction, outperforming the clinical anti-VEGF drug in eliciting sustained therapeutic effect. This study establishes a robust nonviral platform for mRNA delivery and genome editing and renders a promising strategy for CNV treatment.
Insights
Researchers developed novel lipid nanoparticles (LNPs) for gene editing to treat choroidal neovascularization (CNV). This new method effectively reduced CNV and outperformed existing treatments.
Area of Science:
- Biomedical Engineering
- Gene Therapy
- Ophthalmology
Background:
- Current treatments for choroidal neovascularization (CNV) using vascular endothelial growth factor A (VEGFA) inhibitors have limitations.
- These limitations include low response rates, poor patient compliance, and potential ocular damage.
Purpose of the Study:
- To engineer dynamically covalent lipid nanoparticles (LNPs) for VEGFA gene editing and CNV treatment.
- To develop a robust nonviral platform for mRNA delivery and genome editing.
Main Methods:
- Synthesized a library of lipidoids with iminoboronate ester linkages.
- Formulated the top-performing lipidoid (A4B3C7) into LNPs (LNP-A4B3C7) for codelivering Cas9 mRNA (mCas9) and sgRNA targeting VEGFA (sgVEGFA).
- Demonstrated H2O2-triggered LNP dissociation and mRNA/sgRNA release in retinal pigment epithelial cells.
Main Results:
- Achieved high mRNA transfection efficiency with LNP-A4B3C7.
- Showcased enhanced gene editing efficiency due to triggered release.
- In laser-induced CNV mice, a single intravitreal injection of mCas9/sgVEGFA@LNP-A4B3C7 resulted in significant VEGFA disruption and CNV area reduction.
- The LNP treatment demonstrated a sustained therapeutic effect superior to the clinical anti-VEGF drug.
Conclusions:
- Established a robust nonviral platform for mRNA delivery and genome editing.
- Presented a promising therapeutic strategy for treating CNV.
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