A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice
Open accessAbstract
Many genetic liver diseases in newborns cause repeated, often lethal, metabolic crises. Gene therapy using nonintegrating viruses such as adeno-associated virus (AAV) is not optimal in this setting because the nonintegrating genome is lost as developing hepatocytes proliferate. We reasoned that newborn liver may be an ideal setting for AAV-mediated gene correction using CRISPR-Cas9. Here we intravenously infuse two AAVs, one expressing Cas9 and the other expressing a guide RNA and the donor DNA, into newborn mice with a partial deficiency in the urea cycle disorder enzyme, ornithine transcarbamylase (OTC). This resulted in reversion of the mutation in 10% (6.7-20.1%) of hepatocytes and increased survival in mice challenged with a high-protein diet, which exacerbates disease. Gene correction in adult OTC-deficient mice was lower and accompanied by larger deletions that ablated residual expression from the endogenous OTC gene, leading to diminished protein tolerance and lethal hyperammonemia on a chow diet.
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In applications calling for corrective gene insertion, a second AAV vector encoding the sgRNA and/or a template sequence for homology-directed DNA repair must be used, reducing efficiency due to the need for cells to acquire both AAV vectors at once.
“As a result, in applications calling for corrective gene insertion, a second AAV vector encoding the sgRNA and/or a template sequence for homologydirected DNA repair must be used, reducing efficiency due to the need for cells to acquire both AAV vectors at once 59,60 .”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [59]
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Self-citationIn utero CRISPR-mediated therapeutic editing of metabolic genes
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Self-citationIn vivo delivery of CRISPR-Cas9 therapeutics: Progress and challenges
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Self-citationIn vivo RNA editing of point mutations via RNA-guided adenosine deaminases
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Engineered materials for in vivo delivery of genome-editing machinery
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In vivo prime editing of a metabolic liver disease in mice
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“AAVmediated genome editing using CRISPR-Cas9 has been shown to be effective in liver (Ran et al., 2015; Yang et al., 2016), dystrophic muscle (Tabebordbar et al.”
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“To develop in vivo genome-editing protocols [67] and promising somatic gene therapy approaches for devastating degenerative [102–104] or rare [105,106] diseases in animal models.”
BackgroundCRISPR Correction of Duchenne Muscular Dystrophy
Min, Y.-L., Bassel‐Duby, R., & Olson, E. N. (2018) · Annual Review of Medicine · doi:10.1146/annurev-med-081117-010451 · Cited by 189 · see citing works
“For example, a dual-AAV system has been shown to successfully edit hepatocytes and muscle cells in vivo (92).”
Organelle-level precision with next-generation targeting technologies
Saminathan, A., Zajac, M. A., Anees, P., & Krishnan, Y. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00396-8 · Cited by 189 · see citing works
In vivo genome editing improves motor function and extends survival in a mouse model of ALS
Gaj, T., Ojala, D. S., Ekman, F. K., Byrne, L. C., Limsirichai, P., & Schaffer, D. V. (2017) · Science Advances · doi:10.1126/sciadv.aar3952 · Cited by 185 · see citing works
Development of a CRISPR/Cas9-based therapy for Hutchinson–Gilford progeria syndrome
Santiago‐Fernández, O., Osorio, F. G., Quesada, V., Rodríguez, F. J., Basso, S., Maeso, D., Rolas, L., Barkaway, A., Nourshargh, S., Folgueras, A. R., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0338-6 · Cited by 173 · see citing works
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“Multiple AAVs have been used to deliver all three components for targeted gene correction of the mutant gene in preclinical models of ornithine transcarbamylase deficiency [58] and hemophilia B [59].”
MethodDuchenne muscular dystrophy: disease mechanism and therapeutic strategies
Angulski, A. B. B., Hosny, N., Cohen, H., Martin, A. A., Hahn, D., Bauer, J., & Metzger, J. M. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1183101 · Cited by 184 · see citing works
“Hepatocytes and muscle cells have been successfully edited in vivo using a dual-AAV approach (Yang et al., 2016).”
MethodCRISPR-Cas9-mediated homology-directed repair for precise gene editing
Liao, H., Wu, J., VanDusen, N. J., Li, Y., & Zheng, Y. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102344 · Cited by 181 · see citing works
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Delivery approaches for CRISPR/Cas9 therapeutics in vivo: advances and challenges
Luther, D. C., Lee, Y. W., Nagaraj, H., Scaletti, F., & Rotello, V. M. (2018) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2018.1517746 · Cited by 156 · see citing works
CRISPR/Cas: Advances, Limitations, and Applications for Precision Cancer Research
Yang, Y., Xu, J., Ge, S., & Lai, L. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.649896 · Cited by 160 · see citing works
Self-citationImmunity to CRISPR Cas9 and Cas12a therapeutics
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CRISPR-Cas9 for in vivo Gene Therapy: Promise and Hurdles
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Durability of transgene expression after rAAV gene therapy
Muhuri, M., Lévy, D., Schulz, M., McCarty, D. M., & Gao, G. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.03.004 · Cited by 148 · see citing works
Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency
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CRISPR/Cas9 technology as a potent molecular tool for gene therapy
Karimian, A., Azizian, K., Parsian, H., Rafieyan, S., Shafiei‐Irannejad, V., Kheyrollah, M., Yousefi, M., Majidinia, M., & Yousefi, B. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.27972 · Cited by 144 · see citing works
“Another solution was the use of the dual‐AAV system, in which Cas9‐encoding DNA and sgRNA were packed in two AAV vectors separately (Yang et al., 2016).”
MethodCRISPR-Cas9 Targeting of PCSK9 in Human Hepatocytes In Vivo—Brief Report
Wang, X., Raghavan, A., Chen, T., Qiao, L., Zhang, Y., Ding, Q., & Musunuru, K. (2016) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.307227 · Cited by 146 · see citing works
“Pcsk9 gene has previously been the focus of successful in vivo genome-editing studies.(5,6) A demonstration of the efficacy and safety of human PCSK9-targeting therapy in vivo would provide a strong rationale for further preclinical studies with the aim of ultimately bringing to the clinic a one-shot CRISPRCas9 “vacci…”
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Self-citationA Self-Deleting AAV-CRISPR System for In Vivo Genome Editing
Li, A., Lee, C. M., Hurley, A. E., Jarrett, K. E., Giorgi, M. D., Lu, W., Balderrama, K. S., Doerfler, A. M., Deshmukh, H., Ray, A., et al. (2018) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2018.11.009 · Cited by 129 · see citing works
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“Employing a double AAV framework containing SaCas9-encoding sequences, sgRNA-encoding sequences, donor DNA, and OTC editions with homology-directed repair, lead to more survival in mouse models.(58) Duchenne muscular dystrophy (DMD, OMIM #310200) is an acquired X-linked infection caused by changes within the dystrophi…”
BackgroundMethodCRISPR/Cas9‐mediated genome editing: From basic research to translational medicine
Jacinto, F. V., Link, W., & Ferreira, B. I. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14916 · Cited by 130 · see citing works
AAV-mediated CRISPR/cas gene editing of retinal cells in vivo
Hung, S. S. C., Chrysostomou, V., Li, F., Lim, J. K. H., Wang, J.-H., Powell, J. E., Tu, L., Daniszewski, M., Lo, C., Wong, R. C., et al. (2016) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.16-19316 · Cited by 125 · see citing works
Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome
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Therapeutic gene editing: delivery and regulatory perspectives
Shim, G., Kim, D., Park, G. T., Jin, H., Suh, S., & Oh, Y. (2017) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.2 · Cited by 121 · see citing works
CRISPR-Mediated Integration of Large Gene Cassettes Using AAV Donor Vectors
Bak, R. O., & Porteus, M. H. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.06.064 · Cited by 116 · see citing works
“…virus (AAV), can transduce both dividing and non-dividing cells and have recently been effectively used as donor vectors for HR both in vitro and in vivo (Sather et al., 2015, Wang et al., 2015, DeWitt et al., 2016, Yang et al., 2016, Yin et al., 2016, Dever et al., 2016, De Ravin et al., 2017).”
MethodMessenger RNA therapy for rare genetic metabolic diseases
Berraondo, P., Martini, P. G. V., Avila, M. A., & Fontanellas, A. (2019) · Gut · doi:10.1136/gutjnl-2019-318269 · Cited by 118 · see citing works
VSV-G-Enveloped Vesicles for Traceless Delivery of CRISPR-Cas9
Montagna, C., Petris, G., Casini, A., Maule, G., Franceschini, G. M., Zanella, I., Conti, L., Arnoldi, F., Burrone, O. R., Zentilin, L., et al. (2018) · Molecular Therapy Nucleic Acids · doi:10.1016/j.omtn.2018.05.010 · Cited by 117 · see citing works
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CRISPR/Cas9 Genome-Editing System in Human Stem Cells: Current Status and Future Prospects
Zhang, Z., Zhang, Y., Gao, F., Han, S., Cheah, K. S. E., Tse, H., & Lian, Q. (2017) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2017.09.009 · Cited by 116 · see citing works
“This may induce undesired genome damage and ultimately lead to cell death.(145) Although this situation has been resolved by delivering donor (AAV) and CRISPR/Cas9 (transient delivery strategies) separately, the advantages of AAV are partly concealed.”
BackgroundIn vivo genome editing via the HITI method as a tool for gene therapy
Suzuki, K., & Belmonte, J. C. I. (2017) · Journal of Human Genetics · doi:10.1038/s10038-017-0352-4 · Cited by 115 · see citing works
“There are only a few exceptions to this rule, such as the dividing cells of the liver [6, 32, 33].”
Non-Viral Delivery To Enable Genome Editing
Rui, Y., Wilson, D. R., & Green, J. J. (2018) · Trends in biotechnology · doi:10.1016/j.tibtech.2018.08.010 · Cited by 115 · see citing works
CRISPR-Cas12a delivery by DNA-mediated bioresponsive editing for cholesterol regulation
Sun, W., Wang, J., Hu, Q., Zhou, X., Khademhosseini, A., & Gu, Z. (2020) · Science Advances · doi:10.1126/sciadv.aba2983 · Cited by 114 · see citing works
“Potential off-target sites similar to Pcsk9 exon 3 were identified by Benchling ( 55 ).”
In utero gene editing for monogenic lung disease
Alapati, D., Zacharias, W. J., Hartman, H. A., Rossidis, A. C., Stratigis, J. D., Ahn, N. J., Coons, B., Zhou, S., Li, H., Singh, K., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aav8375 · Cited by 123 · see citing works
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“In these experiments, two AAV vectors were injected simultaneously, one of which encoded the transgene and the other the enzymatic system for integration or site specific cutting by Piggybac transposase (Cunningham et al 2015) and CRISPR-Cas9 (Yang et al 2016), respectively.”
MethodIbraheim, R., Tai, P. W. L., Mir, A., Javeed, N., Wang, J., Rodríguez, T., Namkung, S., Nelson, S. J., Khokhar, E. S., Mintzer, E., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26518-y · Cited by 109 · see citing works
The Potential of CRISPR/Cas9 Gene Editing as a Treatment Strategy for Inherited Diseases
Abdelnour, S. A., Xie, L., Hassanin, A. A., Zuo, E., & Lu, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.699597 · Cited by 117 · see citing works
Nanobody-Enhanced Targeting of AAV Gene Therapy Vectors
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CRISPR technologies for stem cell engineering and regenerative medicine
Hsu, M., Chang, Y., Truong, V. A., Lai, P., Nguyen, T. K. N., & Hu, Y. (2019) · Biotechnology Advances · doi:10.1016/j.biotechadv.2019.107447 · Cited by 105 · see citing works
CRISPR/Cas9 for Human Genome Engineering and Disease Research
Xiong, X., Chen, M., Lim, W. A., Zhao, D., & Qi, L. S. (2016) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-083115-022258 · Cited by 105 · see citing works
Carrier strategies boost the application of CRISPR/Cas system in gene therapy
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AAV-Mediated CRISPR/Cas9 Gene Editing in Murine Phenylketonuria
Richards, D. Y., Winn, S. R., Dudley, S., Nygaard, S. C., Mighell, T. L., Grompe, M., & Harding, C. O. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.12.004 · Cited by 101 · see citing works
“Due to the limiting packaging capacity of AAV, this system must be manipulated into two AAV vectors in a dual-AAV approach.(23) Here, one recombinant AAV genome contained the S.”
MethodComprehensive assessment of miniature CRISPR-Cas12f nucleases for gene disruption
Xin, C., Yin, J., Yuan, S., Ou, L., Liu, M., Zhang, W., & Hu, J. (2022) · Nature Communications · doi:10.1038/s41467-022-33346-1 · Cited by 95 · see citing works
Functional variomics and network perturbation: connecting genotype to phenotype in cancer
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CRISPR/Cas System and Factors Affecting Its Precision and Efficiency
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“2 For Cas9 mRNA and Protein Cas9 and sgRNA show persistent expression when delivered in the form of a cloned vector (Xue et al., 2014a; Yin et al., 2014; Yang et al., 2016); however, it might cause mutation with random integration of CRISPR components at on-target and off-target sites into the host genome (Cradick et…”
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In Vivo Ryr 2 Editing Corrects Catecholaminergic Polymorphic Ventricular Tachycardia
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The Promise and Challenge of In Vivo Delivery for Genome Therapeutics
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Genome editing in cardiovascular diseases
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Self-citationGene Therapy in the Anterior Eye Segment
Amador, C., Shah, R., Ghiam, S., Kramerov, A. A., & Ljubimov, A. V. (2021) · Current Gene Therapy · doi:10.2174/1566523221666210423084233 · Cited by 89 · see citing works
- Authors
- Yang, Y., Wang, L., Bell, P., McMenamin, D., He, Z., White, J., Yu, H., Xu, C., Morizono, H., Musunuru, K., Batshaw, M. L., & Wilson, J. M.
- Affiliations
- Sichuan University (CN)
- University of Pennsylvania (US)
- Children's National (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Wilson, James M
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2016-02-01
- Volume
- 34
- Issue
- 3
- Pages
- 334-338
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC4786489
- OpenAlex
- W2253584908
- Cited by
- 556
- References
- 36
- Citations by year
- 2026: 20 · 2025: 25 · 2024: 36 · 2023: 52 · 2022: 55 · 2021: 61 · 2020: 70 · 2019: 62 · 2018: 72 · 2017: 71 · 2016: 30 · 2014: 1
- FWCI
- 63.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD057247)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- 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
- Keywords
- adeno-associated virus, CRISPR/Cas9, gene correction, ornithine transcarbamylase deficiency, urea cycle disorders, neonatal mice, liver disease, hyperammonemia, high-protein diet, hepatocytes, gene therapy
- MeSH terms
- Dependovirus, Animals, Disease Models, Animal, Genetic Vectors, Humans, Ornithine Carbamoyltransferase, Viruses, RNA Editing, Gene Transfer Techniques, Ornithine Carbamoyltransferase Deficiency Disease, Mice, CRISPR-Cas Systems
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