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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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“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]
Experimental — accuracy not yet measuredIn the citing paper
“Currently, researchers most frequently employ a dual AAV system for CRISPR-mediated gene correction: one AAV expresses Cas9 while the other expresses the sgRNA and donor template DNA [24].”
From Viral Delivery Systems for CRISPR (2019) · cites this paper as [24]
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“Furthermore, there was an increase in survival of mice with a high-protein diet, a stressor which exacerbates this in-born error of metabolism.”
From Viral Delivery Systems for CRISPR (2019) · cites this paper as [24]
In the citing paper
“After AAV delivery, these mice experienced a reversion of the mutation in 10% of their hepatocytes.”
From Viral Delivery Systems for CRISPR (2019) · cites this paper as [24]
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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 135
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
Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome
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In utero gene editing for monogenic lung disease
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Self-citationTherapeutic gene editing: delivery and regulatory perspectives
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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 124
“…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 121
VSV-G-Enveloped Vesicles for Traceless Delivery of CRISPR-Cas9
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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 122
“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 122
“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
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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 115
“Potential off-target sites similar to Pcsk9 exon 3 were identified by Benchling ( 55 ).”
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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 112
The Potential of CRISPR/Cas9 Gene Editing as a Treatment Strategy for Inherited Diseases
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Nanobody-Enhanced Targeting of AAV Gene Therapy Vectors
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CRISPR technologies for stem cell engineering and regenerative medicine
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CRISPR/Cas9 for Human Genome Engineering and Disease Research
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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
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“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
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
Metadata
- 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
- 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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