Targeted Knockout of the Vegfa Gene in the Retina by Subretinal Injection of RNP Complexes Containing Cas9 Protein and Modified SgRNAs
Open accessAbstract
The therapeutic effect of retinal gene therapy using CRISPR/Cas9-mediated genome editing and knockout applications is dependent on efficient and safe delivery of gene-modifying tool kits. Recently, transient administration of single guide RNAs (sgRNAs) and SpCas9 proteins delivered as ribonucleoproteins (RNPs) has provided potent gene knockout in vitro. To improve efficacy of CRISPR-based gene therapy, we delivered RNPs containing SpCas9 protein complexed to chemically modified sgRNAs (msgRNAs). In K562 cells, msgRNAs significantly increased the insertion/deletion (indel) frequency (25%) compared with unmodified counterparts leading to robust knockout of the VEGFA gene encoding vascular endothelial growth factor A (96% indels). Likewise, in HEK293 cells, lipoplexes containing varying amounts of RNP and EGFP mRNA showed efficient VEGFA knockout (43% indels) and strong EGFP expression, indicative of efficacious functional knockout using small amounts of RNP. In mice, subretinal injections of equivalent lipoplexes yielded 6% indels in Vegfa of isolated EGFP-positive RPE cells. However, signs of toxicity following delivery of lipoplexes containing high amounts of RNP were observed. Although the mechanism resulting in the varying efficacy remains to be elucidated, our data suggest that a single subretinal injection of RNPs carrying msgRNAs and SpCas9 induces targeted retinal indel formation, thus providing a clinically relevant strategy relying on nonviral delivery of short-lived nuclease activity.
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Preservation of RO outer segments and RPE morphology was observed following Lipofectamine treatment, unlike electroporation and previously reported data using lipid-based transfection.
“In this context, we observed preservation of RO outer segments and RPE morphology following Lipofectamine treatment, unlike electroporation and previously reported data using lipid-based transfection [43].”
From Precise CRISPR/Cas9 and Cas12 Correction Using Lipoplexes in Retinal Models Derived from Patients with Inherited Retinal Dystrophies (2026) · cites this paper as [43]
The cited paper’s Results section reports altered RPE cell morphology after subretinal delivery of LF3000 lipid-based lipoplexes containing high amounts of Cas9 RNP, supporting the comparison concerning RPE morphology. It does not report loss of retinal organoid outer segments or compare lipid-based transfection with electroporation; the citing authors’ own observation of preservation is not attributed to this source. No page number is available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn mice receiving lipoplexes carrying RNP-SpCas9 and sgRNA targeting Vegfa, GFP expression and indel formation frequency increased with quantity injected, peaked, and decreased at higher doses.
“The GFP expression and indel formation frequency increased with the quantity injected, reached a peak and then started to decrease if higher doses were used.”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [76]
Increased autofluorescence was found in RPE cells as a sign of toxicity following delivery of lipoplexes containing high amounts of RNP.
“Increased autofluorescence was found in RPE cells as a sign of toxicity following the delivery of lipoplexes containing high amounts of RNP [76].”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [76]
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Gene therapy for diabetic retinopathy
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He, M., Dong, N., Zhang, L., Wang, Y., Wu, H., Fang, H., & Tian, H. (2026) · Chinese Chemical Letters · doi:10.1016/j.cclet.2026.112939
- Authors
- Holmgaard, A. B., Askou, A. L., Jensen, E. G., Alsing, S., Bak, R. O., Mikkelsen, J. G., & Corydon, T. J.
- Affiliations
- Aarhus University (DK)
- Corresponding author
- Corydon, Thomas J.
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 29
- Issue
- 1
- Pages
- 191-207
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC7791085
- OpenAlex
- W3088061065
- Cited by
- 36
- References
- 45
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 4 · 2023: 10 · 2022: 8 · 2021: 3
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Danish Eye Research Foundation
- Aarhus Universitet
- Aase og Ejnar Danielsens Fond
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- VEGF-A, CRISPR/Cas9, ribonucleoprotein complexes, SpCas9, subretinal injection, lipoplexes, retinal gene therapy, retinal pigment epithelium, indel frequency, non-viral gene delivery, retinal toxicity
- MeSH terms
- Gene Editing, RNA, Guide, CRISPR-Cas Systems, Animals, Cell Line, Humans, Retina, Ribonucleoproteins, Transfection, Genetic Therapy, Gene Transfer Techniques, Vascular Endothelial Growth Factor A, Mice, Gene Knockout Techniques, CRISPR-Cas Systems
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