Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours
Open accessAbstract
Technologies that can safely edit genes in the brains of adult animals may revolutionize the treatment of neurological diseases and the understanding of brain function. Here, we demonstrate that intracranial injection of CRISPR-Gold, a nonviral delivery vehicle for the CRISPR-Cas9 ribonucleoprotein, can edit genes in the brains of adult mice in multiple mouse models. CRISPR-Gold can deliver both Cas9 and Cpf1 ribonucleoproteins, and can edit all of the major cell types in the brain, including neurons, astrocytes and microglia, with undetectable levels of toxicity at the doses used. We also show that CRISPR-Gold designed to target the metabotropic glutamate receptor 5 (mGluR5) gene can efficiently reduce local mGluR5 levels in the striatum after an intracranial injection. The effect can also rescue mice from the exaggerated repetitive behaviours caused by fragile X syndrome, a common single-gene form of autism spectrum disorders. CRISPR-Gold may significantly accelerate the development of brain-targeted therapeutics and enable the rapid development of focal brain-knockout animal models.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CRISPR-Gold was able to edit a target gene and rescue increased repetitive behaviors in a mouse model for fragile X syndrome by injecting directly into the striatum.
“Lee et al. (2018) further demonstrated that CRISPR-Gold which contains gold nanoparticles and Cas9 RNPs was able to successfully edit target gene and rescue increased repetitive behaviors in a mouse model for fragile X syndrome, a neurodevelopmental disorder (33). This was achieved by injecting directly into the striatum (33).”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [33]
Through intracranial injection of 2 μL CRISPR-Gold, both mRNA and protein levels of mGluR5 decreased 40-50% in FXS mice.
“Through intracranial injection of 2 μL of CRISPR-Gold, both the mRNA and protein levels of mGluR5 decreased 40–50% in FXS mice.”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [44]
Treated FXS mice significantly resumed exaggerated repetitive behaviors after three weeks.
“Furthermore, the treated FXS mice significantly resumed exaggerated repetitive behaviors after three weeks.[44]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [44]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity
Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012) · Science · doi:10.1126/science.1225829 · Cited by 17,116 · see citing works
Multiplex Genome Engineering Using CRISPR/Cas Systems
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., et al. (2013) · Science · doi:10.1126/science.1231143 · Cited by 15,339 · see citing works
RNA-Guided Human Genome Engineering via Cas9
Mali, P., Yang, L., Esvelt, K. M., Aach, J., Guell, M., DiCarlo, J. E., Norville, J. E., & Church, G. M. (2013) · Science · doi:10.1126/science.1232033 · Cited by 9,210 · see citing works
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907 · see citing works
Improved vectors and genome-wide libraries for CRISPR screening
Sanjana, N. E., Shalem, O., & Zhang, F. (2014) · Nature Methods · doi:10.1038/nmeth.3047 · Cited by 5,239 · see citing works
Cpf1 Is a Single RNA-Guided Endonuclease of a Class 2 CRISPR-Cas System
Zetsche, B., Gootenberg, J. S., Abudayyeh, O. O., Slaymaker, I. M., Makarova, K. S., Essletzbichler, P., Volz, S. E., Joung, J., John van der, O. O. S. T., Regev, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.09.038 · Cited by 4,750 · see citing works
Imaging Neuronal Subsets in Transgenic Mice Expressing Multiple Spectral Variants of GFP
Feng, G., Mellor, R. H., Bernstein, M., Keller-Peck, C., Nguyen, Q. T., Wallace, M., Nerbonne, J. M., Lichtman, J. W., & Sanes, J. R. (2000) · Neuron · doi:10.1016/s0896-6273(00)00084-2 · Cited by 3,042 · see citing works
Easy quantitative assessment of genome editing by sequence trace decomposition
Brinkman, E. K., Chen, T., Amendola, M., & van Steensel, B. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku936 · Cited by 2,390 · see citing works
Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease
Cho, S. W., Kim, S., Kim, J. M., & Kim, J.-S. (2013) · Nature Biotechnology · doi:10.1038/nbt.2507 · Cited by 1,863 · see citing works
The mGluR theory of fragile X mental retardation
Bear, M. F., Huber, K. M., & Warren, S. T. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.04.009 · Cited by 1,580 · see citing works
Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery
Lin, S., Staahl, B. T., Alla, R. K., & Doudna, J. A. (2014) · eLife · doi:10.7554/elife.04766 · Cited by 1,189 · see citing works
In vivo gene editing in dystrophic mouse muscle and muscle stem cells
Tabebordbar, M., Zhu, K., Cheng, J. K. W., Chew, W. L., Widrick, J. J., Yan, W. X., Maesner, C., Wu, E. Y., Xiao, R., Ran, F. A., et al. (2016) · Science · doi:10.1126/science.aad5177 · Cited by 1,046 · see citing works
Immune responses to AAV vectors: overcoming barriers to successful gene therapy
Mingozzi, F., & High, K. A. (2013) · Blood · doi:10.1182/blood-2013-01-306647 · Cited by 955 · see citing works
Autism‐like behavioral phenotypes in BTBR T+tf/J mice
McFarlane, H. G., Kusek, G. K., Yang, M., Phoenix, J. L., Bolivar, V. J., & Crawley, J. N. (2008) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2007.00330.x · Cited by 812 · see citing works
In vivo interrogation of gene function in the mammalian brain using CRISPR-Cas9
Swiech, L., Heidenreich, M., Banerjee, A., Habib, N., Li, Y., Trombetta, J., Sur, M., & Zhang, F. (2015) · Nature Biotechnology · doi:10.1038/nbt.3055 · Cited by 772 · cited 5× · see citing works
“Currently, gene editing in the adult brain is mainly accomplished through the viral delivery of CRISPR-Cas9 6 .”
BackgroundInfluentialLee, K., Conboy, M., Park, H. M., Jiang, F., Kim, H. J., Dewitt, M. A., Mackley, V. A., Chang, K., Rao, A., Skinner, C., et al. (2017) · Nature Biomedical Engineering · doi:10.1038/s41551-017-0137-2 · Cited by 755 · see citing works
Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety
Thomas, A., Burant, A., Bui, N., Graham, D., Yuva-Paylor, L. A., & Paylor, R. (2009) · Psychopharmacology · doi:10.1007/s00213-009-1466-y · Cited by 698 · see citing works
Jacquemont, S., Curie, A., des Portes, V., Torrioli, M. G., Berry-Kravis, E., Hagerman, R. J., Ramos, F. J., Cornish, K., He, Y., Paulding, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3001708 · Cited by 609 · see citing works
Zhang, X., Servos, M. R., & Liu, J. (2012) · Journal of the American Chemical Society · doi:10.1021/ja3014055 · Cited by 590 · see citing works
Fried, I., Mukamel, R., & Kreiman, G. (2011) · Neuron · doi:10.1016/j.neuron.2010.11.045 · Cited by 459 · see citing works
Osterweil, E. K., Krueger, D. D., Reinhold, K., & Bear, M. F. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3888-10.2010 · Cited by 384 · see citing works
Miyata, K., Oba, M., Nakanishi, M., Fukushima, S., Yamasaki, Y., Koyama, H., Nishiyama, N., & Kataoka, K. (2008) · Journal of the American Chemical Society · doi:10.1021/ja804561g · Cited by 372 · see citing works
Staahl, B. T., Benekareddy, M., Coulon-Bainier, C., Banfal, A. A., Floor, S. N., Sabo, J. K., Urnes, C., Munares, G. A., Ghosh, A., & Doudna, J. A. (2017) · Nature Biotechnology · doi:10.1038/nbt.3806 · Cited by 355 · see citing works
Watakabe, A., Ohtsuka, M., Kinoshita, M., Takaji, M., Isa, K., Mizukami, H., Ozawa, K., Isa, T., & Yamamori, T. (2015) · Neuroscience Research · doi:10.1016/j.neures.2014.09.002 · Cited by 303 · see citing works
Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome
Dölen, G., & Bear, M. F. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.150722 · Cited by 278 · see citing works
Silverman, J. L., Smith, D. G., Rizzo, S. J. S., Karras, M. N., Turner, S. M., Tolu, S. S., Bryce, D. K., Smith, D. L., Fonseca, K., Ring, R. H., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003501 · Cited by 251 · see citing works
Persico, A. M., & Napolioni, V. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.06.012 · Cited by 242 · see citing works
Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse
Kazdoba, T. M., Leach, P. T., Silverman, J. L., & Crawley, J. N. (2014) · Intractable & Rare Diseases Research · doi:10.5582/irdr.2014.01024 · Cited by 241 · see citing works
Driving Opposing Behaviors with Ensembles of Piriform Neurons
Choi, G. B., Stettler, D. D., Kallman, B. R., Bhaskar, S., Fleischmann, A., & Axel, R. (2011) · Cell · doi:10.1016/j.cell.2011.07.041 · Cited by 232 · see citing works
Spencer, C. M., Alekseyenko, O. V., Hamilton, S. M., Thomas, A. M., Serysheva, E., Yuva‐Paylor, L. A., & Paylor, R. E. (2011) · Autism Research · doi:10.1002/aur.168 · Cited by 215 · see citing works
Park, C.-Y., Halevy, T., Lee, D. R., Sung, J. J., Lee, J. S., Yanuka, O., Benvenisty, N., & Kim, D.-W. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.08.084 · Cited by 178 · see citing works
Lee, H. Y., Ge, W., Huang, W. C., He, Y., Wang, G. X., Rowson-Baldwin, A., Smith, S. J., Jan, Y. N., & Jan, L. Y. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.033 · Cited by 149 · see citing works
Macrophages in gene therapy: cellular delivery vehicles and in vivo targets
Burke, B., Sumner, S., Maitland, N. J., & Lewis, C. E. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.72.3.417 · Cited by 148 · see citing works
Kim, H., Lim, C., & Kaang, B. (2016) · Behavioral and Brain Functions · doi:10.1186/s12993-016-0087-y · Cited by 146 · see citing works
Genome editing assessment using CRISPR Genome Analyzer (CRISPR-GA)
Güell, M., Yang, L., & Church, G. M. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu427 · Cited by 142 · see citing works
Graham, D. R., & Sidhu, A. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22331 · Cited by 137 · see citing works
Therapeutic implications of the mGluR theory of fragile X mental retardation
Bear, M. F. (2005) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2005.00135.x · Cited by 137 · see citing works
Xie, N., Gong, H., Suhl, J. A., Chopra, P., Wang, T., & Warren, S. T. (2016) · PLoS ONE · doi:10.1371/journal.pone.0165499 · Cited by 123 · see citing works
Behavioral analysis of male and female Fmr1 knockout mice on C57BL/6 background
Ding, Q., Sethna, F., & Wang, H. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.05.046 · Cited by 121 · see citing works
Kim, H. J., Ishii, A., Miyata, K., Lee, Y., Wu, S., Oba, M., Nishiyama, N., & Kataoka, K. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.03.019 · Cited by 119 · see citing works
Generating Primary Fibroblast Cultures from Mouse Ear and Tail Tissues
Khan, M., & Gasser, S. (2016) · Journal of Visualized Experiments · doi:10.3791/53565 · Cited by 95 · see citing works
Pharmacotherapy for mental health problems in people with intellectual disability
Ji, N. Y., & Findling, R. L. (2016) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000233 · Cited by 77 · see citing works
Psychopharmacological Interventions in Autism Spectrum Disorder
Politte, L. C., Henry, C. A., & McDougle, C. J. (2014) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000030 · Cited by 73 · see citing works
Sungur, A. Ö., Vörckel, K. J., Schwarting, R. K. W., & Wöhr, M. (2014) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2014.05.003 · Cited by 70 · see citing works
Rizzo, S. J. S., & Crawley, J. N. (2017) · Annual Review of Animal Biosciences · doi:10.1146/annurev-animal-022516-022754 · Cited by 66 · see citing works
Public Health Literature Review of Fragile X Syndrome
Raspa, M., Wheeler, A., & Riley, C. M. (2017) · PEDIATRICS · doi:10.1542/peds.2016-1159c · Cited by 61 · see citing works
Size-dependent impairment of cognition in mice caused by the injection of gold nanoparticles
Chen, Y.-S., Hung, Y., Lin, L.-W., Liau, I., Hong, M., & Huang, G. S. (2010) · Nanotechnology · doi:10.1088/0957-4484/21/48/485102 · Cited by 54 · see citing works
Tao, J., Wu, H., Coronado, A. A., de Laittre, E. A., Osterweil, E. K., Zhang, Y., & Bear, M. F. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.0672-16.2016 · Cited by 42 · see citing works
Minimizing off-Target Mutagenesis Risks Caused by Programmable Nucleases
Ishida, K., Gee, P., & Hotta, A. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161024751 · Cited by 41 · see citing works
Lentiviral transduction of microglial cells
Balcaitis, S. D., Weinstein, J. R., Li, S., Chamberlain, J. S., & Möller, T. (2004) · Glia · doi:10.1002/glia.20146 · Cited by 41 · see citing works
Ferreira, G. K., Cardoso, E., Vuolo, F. S., Galant, L. S., Michels, M., Gonçalves, C. L., Rezin, G. T., Dal‐Pizzol, F., Benavides, R., Alonso-Núñez, G., et al. (2017) · Materials Science and Engineering C · doi:10.1016/j.msec.2017.05.110 · Cited by 32 · see citing works
Gene-editing therapy for neurological disease
McMahon, M. A., & Cleveland, D. W. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.190 · Cited by 28 · see citing works
Glia: an emerging target for neurological disease therapy
Almad, A. A., & Maragakis, N. J. (2012) · Stem Cell Research & Therapy · doi:10.1186/scrt128 · Cited by 27 · see citing works
Lentiviral Transduction of Cultured Microglia
Masuda, T., Tsuda, M., Tozaki‐Saitoh, H., & Inoue, K. (2013) · Methods in molecular biology · doi:10.1007/978-1-62703-520-0_8 · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Drug delivery systems for RNA therapeutics
Paunovska, K., Loughrey, D., & Dahlman, J. E. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-021-00439-4 · Cited by 1,349 · see citing works
Wei, T., Cheng, Q., Min, Y.-L., Olson, E. N., & Siegwart, D. J. (2020) · Nature Communications · doi:10.1038/s41467-020-17029-3 · Cited by 603 · see citing works
Base editing: advances and therapeutic opportunities
Porto, E. M., Komor, A. C., Slaymaker, I. M., & Yeo, G. W.-M. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0084-6 · Cited by 475 · see citing works
Strategies in the delivery of Cas9 ribonucleoprotein for CRISPR/Cas9 genome editing
Zhang, S., Shen, J., Li, D., & Cheng, Y. (2021) · Theranostics · doi:10.7150/thno.47007 · Cited by 430 · see citing works
Nanoparticle Delivery of CRISPR/Cas9 for Genome Editing
Duan, L., Ouyang, K., Xu, X. G., Xu, L., Wen, C., Zhou, X., Qin, Z., Xu, Z., Sun, W., & Liang, Y. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.673286 · Cited by 400 · see citing works
Delivery of drugs, proteins, and nucleic acids using inorganic nanoparticles
Luther, D. C., Huang, R., Jeon, T., Zhang, X., Lee, Y.-W., Nagaraj, H., & Rotello, V. M. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.06.020 · Cited by 372 · see citing works
Sago, C. D., Lokugamage, M. P., Paunovska, K., Vanover, D. A., Monaco, C. M., Shah, N. N., Gamboa Castro, M., Anderson, S. E., Rudoltz, T. G., Lando, G. N., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811276115 · Cited by 313 · see citing works
Kenjo, E., Hozumi, H., Makita, Y., Iwabuchi, K. A., Fujimoto, N., Matsumoto, S., Kimura, M., Amano, Y., Ifuku, M., Naoe, Y., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26714-w · Cited by 305 · see citing works
The delivery challenge: fulfilling the promise of therapeutic genome editing
van Haasteren, J., Li, J., Scheideler, O. J., Murthy, N., & Schaffer, D. V. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0565-5 · Cited by 285 · see citing works
Polymers for cytosolic protein delivery
Lv, J., Fan, Q., Wang, H., & Cheng, Y. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119358 · Cited by 264 · see citing works
Kaushik, A. K., Yndart, A., Atluri, V. S. R., Tiwari, S., Tomitaka, A., Gupta, P., Jayant, R. D., Alvarez-Carbonell, D., Khalili, K., & Nair, M. G. (2019) · Scientific Reports · doi:10.1038/s41598-019-40222-4 · Cited by 255 · see citing works
Wang, G., Zhao, X., Wu, H., Lovejoy, D. B., Zheng, M., Lee, A., Fu, L., Miao, K., An, Y., Sayyadi, N., et al. (2020) · Small · doi:10.1002/smll.202003654 · Cited by 236 · see citing works
Cell-Type-Specific CRISPR/Cas9 Delivery by Biomimetic Metal Organic Frameworks
Alyami, M., Alsaiari, S. K., Li, Y., Qutub, S., Aleisa, F. A., Sougrat, R., Merzaban, J. S., & Khashab, N. M. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.9b11638 · Cited by 228 · see citing works
Zou, Y., Sun, X., Yang, Q., Zheng, M., Shimoni, O., Ruan, W., Wang, Y., Zhang, D., Yin, J., Huang, X., et al. (2022) · Science Advances · doi:10.1126/sciadv.abm8011 · Cited by 227 · see citing works
Engineered materials for in vivo delivery of genome-editing machinery
Tong, S., Moyo, B., Lee, C. M., Leong, K. W., & Bao, G. (2019) · Nature Reviews Materials · doi:10.1038/s41578-019-0145-9 · Cited by 206 · see citing works
Strategies for nonviral nanoparticle‐based delivery of CRISPR/Cas9 therapeutics
Chen, F., Alphonse, M., & Liu, Q. (2020) · WIREs Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1609 · Cited by 197 · see citing works
CRISPR Cpf1 proteins: structure, function and implications for genome editing
Safari, F., Zare, K., Negahdaripour, M., Barekati‐Mowahed, M., & Ghasemi, Y. (2019) · Cell & Bioscience · doi:10.1186/s13578-019-0298-7 · Cited by 196 · see citing works
Targeting herpes simplex virus with CRISPR–Cas9 cures herpetic stromal keratitis in mice
Yin, D., Ling, S., Wang, D., Dai, Y., Jiang, H., Zhou, X., Paludan, S. R., Hong, J., & Cai, Y. (2021) · Nature Biotechnology · doi:10.1038/s41587-020-00781-8 · Cited by 188 · see citing works
Rational designs of in vivo CRISPR-Cas delivery systems
Xu, C., Chen, G., Luo, Y., Zhang, Y., Zhao, G., Lu, Z.-D., Czarna, A., Gu, Z., & Wang, J. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.11.005 · Cited by 185 · see citing works
Ling, S., Yang, S., Hu, X., Yin, D., Dai, Y., Qian, X., Wang, D., Pan, X., Hong, J., Sun, X., et al. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-020-00656-y · Cited by 182 · see citing works
Drug delivery systems for CRISPR-based genome editors
Madigan, V. J., Zhang, F., & Dahlman, J. E. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00762-x · Cited by 180 · see citing works
Lung and liver editing by lipid nanoparticle delivery of a stable CRISPR–Cas9 ribonucleoprotein
Chen, K., Han, H., Zhao, S., Xu, B., Yin, B., Lawanprasert, A., Trinidad, M. I., Burgstone, B. W., Murthy, N., & Doudna, J. A. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02437-3 · Cited by 185 · see citing works
Targeted homology-directed repair in blood stem and progenitor cells with CRISPR nanoformulations
Shahbazi, R., Sghia-Hughes, G., Reid, J. L., Kubek, S., Haworth, K. G., Humbert, O., Kiem, H., & Adair, J. E. (2019) · Nature Materials · doi:10.1038/s41563-019-0385-5 · Cited by 158 · see citing works
CRISPR-Cas for genome editing: Classification, mechanism, designing and applications
Bhatia, S. K., ., P., & Yadav, S. K. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.124054 · Cited by 165 · see citing works
Recent Advances in Stimulus‐Responsive Nanocarriers for Gene Therapy
Cheng, Y., Li, L., Hu, P., Yang, Y., Wei, W., Deng, X., Wang, L., Tay, F. R., & Ma, J. (2021) · Advanced Science · doi:10.1002/advs.202100540 · Cited by 160 · see citing works
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
Delivery of CRISPR/Cas9 for therapeutic genome editing
Xu, X., Wan, T. Y., Xin, H., Li, D., Pan, H., Wu, J., & Yuan, P. (2019) · The Journal of Gene Medicine · doi:10.1002/jgm.3107 · Cited by 147 · see citing works
Li, F., Song, N., Dong, Y., Li, S., Li, L., Liu, Y., Li, Z., & Yang, D. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202116569 · Cited by 145 · see citing works
A Self-Assembled Platform Based on Branched DNA for sgRNA/Cas9/Antisense Delivery
Liu, J., Wu, T., Lu, X., Wu, X., Liu, S., Zhao, S., Xu, X., & Ding, B. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b09043 · Cited by 140 · see citing works
Fast microwave heating-based one-step synthesis of DNA and RNA modified gold nanoparticles
Huang, M., Xiong, E., Wang, Y., Hu, M., Yue, H., Tian, T., Zhu, D., Liu, H. S., & Zhou, X. (2022) · Nature Communications · doi:10.1038/s41467-022-28627-8 · Cited by 138 · see citing works
Wei, T., Cheng, Q., Farbiak, L., Anderson, D. G., Langer, R., & Siegwart, D. J. (2020) · ACS Nano · doi:10.1021/acsnano.0c04707 · Cited by 137 · see citing works
Nanomaterials for Therapeutic RNA Delivery
Han, X., Mitchell, M. J., & Nie, G. (2020) · Matter · doi:10.1016/j.matt.2020.09.020 · Cited by 137 · see citing works
Guo, J., Wan, T. Y., Li, B., Pan, Q., Xin, H., Qiu, Y., & Yuan, P. (2021) · ACS Central Science · doi:10.1021/acscentsci.0c01648 · Cited by 135 · see citing works
A review on biological and biomimetic materials and their applications
Kumar, N. S., Suvarna, R. P., Naidu, K. C. B., Banerjee, P., Ratnamala, A., & Manjunatha, H. (2020) · Applied Physics A · doi:10.1007/s00339-020-03633-z · Cited by 132 · see citing works
Kumar, R., Le, N., Tan, Z., Brown, M. E., Jiang, S., & Reineke, T. M. (2020) · ACS Nano · doi:10.1021/acsnano.0c08549 · Cited by 127 · see citing works
Rohiwal, S. S., Dvořáková, N., Klı́ma, J., Vaškovičová, M., Šenigl, F., Šlouf, M., Pavlová, E., Štěpánek, P., Babuka, D., Beneš, H., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-61465-6 · Cited by 122 · see citing works
Wan, T. Y., Niu, D., Wu, C., Xu, F., Church, G. M., & Yuan, P. (2019) · Materials Today · doi:10.1016/j.mattod.2018.12.003 · Cited by 118 · see citing works
Liu, W., Rudis, M. R., Cheplick, M. H., Millwood, R. J., Yang, J., Ondzighi‐Assoume, C. A., Montgomery, G. A., Burris, K. P., Mazarei, M., Chesnut, J. D., et al. (2019) · Plant Cell Reports · doi:10.1007/s00299-019-02488-w · Cited by 116 · see citing works
Nucleic acid nanoassembly-enhanced RNA therapeutics and diagnosis
Zhao, M., Wang, R., Yang, K., Jiang, Y., Peng, Y., Li, Y., Zhang, Z., Ding, J., & Shi, S. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.10.019 · Cited by 117 · see citing works
Asimakidou, E., Tan, J. K. S., Zeng, J., & Lo, C. H. (2024) · Pharmaceuticals · doi:10.3390/ph17050612 · Cited by 115 · see citing works
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
Sharpening the Molecular Scissors: Advances in Gene-Editing Technology
Broeders, M., Herrero-Hernandez, P., Ernst, M. P. T., van der Ploeg, A. T., & Pijnappel, W. W. M. P. (2019) · iScience · doi:10.1016/j.isci.2019.100789 · Cited by 110 · see citing works
Protein Delivery into the Cell Cytosol using Non-Viral Nanocarriers
Lee, Y.-W., Luther, D. C., Kretzmann, J. A., Burden, A., Jeon, T., Zhai, S., & Rotello, V. M. (2019) · Theranostics · doi:10.7150/thno.34412 · Cited by 107 · see citing works
Nucleic acid drug vectors for diagnosis and treatment of brain diseases
Lü, Z., Shen, J., Yang, H. J., Wang, J., Zhao, R., Zhang, T.-L., Guo, J. R., & Zhang, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01298-z · Cited by 108 · see citing works
Xu, F., Mu, J., Teng, Y., Zhang, X., Sundaram, K., Sriwastva, M. K., Kumar, A., Lei, C., Zhang, L., Liu, Q. M., et al. (2021) · Small · doi:10.1002/smll.202105385 · Cited by 103 · see citing works
Carrier strategies boost the application of CRISPR/Cas system in gene therapy
Xu, Z., Wang, Q., Zhong, H., Jiang, Y., Shi, X., Yuan, B., Yu, N., Zhang, S., Yuan, X., Guo, S., et al. (2022) · Exploration · doi:10.1002/exp.20210081 · Cited by 104 · see citing works
Ultrasound-Controlled CRISPR/Cas9 System Augments Sonodynamic Therapy of Hepatocellular Carcinoma
Yin, H., Sun, L., Pu, Y., Yu, J., Feng, W., Dong, C., Zhou, B., Du, D., Zhang, Y., Chen, Y., et al. (2021) · ACS Central Science · doi:10.1021/acscentsci.1c01143 · Cited by 101 · see citing works
A neuroscientist’s guide to transgenic mice and other genetic tools
Navabpour, S., Kwapis, J. L., & Jarome, T. J. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.12.013 · Cited by 101 · see citing works
Mashel, T., Tarakanchikova, Y., Muslimov, A., Zyuzin, M., Timin, A., Lepik, K., & Fehse, B. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120282 · Cited by 92 · see citing works
Wan, F., Draz, M. S., Gu, M., Yu, W., Ruan, Z., & Luo, Q. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13030352 · Cited by 103 · see citing works
Challenges in delivery systems for CRISPR-based genome editing and opportunities of nanomedicine
Sioson, V. A., Kim, M., & Joo, J. (2021) · Biomedical Engineering Letters · doi:10.1007/s13534-021-00199-4 · Cited by 115 · see citing works
Single-atom nanozymes for biological applications
Pei, J., Zhao, R., Mu, X., Wang, J., Liu, C., & Zhang, X. (2020) · Biomaterials Science · doi:10.1039/d0bm01447h · Cited by 98 · see citing works
Abbasi, S., Uchida, S., Toh, K., Tockary, T. A., Dirisala, A., Hayashi, K., Fukushima, S., & Kataoka, K. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.02.026 · Cited by 99 · see citing works
Wang, Q., & Coleman, J. J. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.06.007 · Cited by 97 · see citing works
Chen, Q., Zhang, Y., & Yin, H. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.10.014 · Cited by 96 · see citing works
CRISPR/Cas9 Delivery System Engineering for Genome Editing in Therapeutic Applications
Cheng, H., Zhang, F., & Ding, Y. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13101649 · Cited by 98 · see citing works
Neural Mechanisms Underlying Repetitive Behaviors in Rodent Models of Autism Spectrum Disorders
Gandhi, T., & Lee, C. C. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.592710 · Cited by 94 · see citing works
CRISPR/Cas systems: Delivery and application in gene therapy
Huang, J., Zhou, Y., Li, J., Lü, A., & Liang, C. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.942325 · Cited by 93 · see citing works
Ling, S., Zhang, X., Dai, Y., Jiang, Z., Zhou, X., Lu, S., Qian, X., Liu, J., Selfjord, N., Şatır, T. M., et al. (2025) · Nature Nanotechnology · doi:10.1038/s41565-024-01851-7 · Cited by 97 · see citing works
Drug delivery using gold nanoparticles
Dykman, L. A., Khlebtsov, B. N., & Khlebtsov, N. G. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115481 · Cited by 93 · see citing works
Biomaterials as vectors for the delivery of CRISPR–Cas9
Eoh, J. H., & Gu, L. (2019) · Biomaterials Science · doi:10.1039/c8bm01310a · Cited by 91 · see citing works
Nanotechnology for pain management: Current and future therapeutic interventions
Bhansali, D., Teng, S. L., Lee, C. S., Schmidt, B. L., Bunnett, N. W., & Leong, K. W. (2021) · Nano Today · doi:10.1016/j.nantod.2021.101223 · Cited by 85 · see citing works
Dubey, A. K., Gupta, V. K., Kujawska, M., Orive, G., Kim, N., Li, C.-Z., Mishra, Y. K., & Kaushik, A. K. (2022) · Journal of nanostructure in chemistry · doi:10.1007/s40097-022-00472-7 · Cited by 86 · see citing works
Spatiotemporal Delivery of CRISPR/Cas9 Genome Editing Machinery Using Stimuli‐Responsive Vehicles
Cai, W., Luo, T., Mao, L., & Wang, M. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202005644 · Cited by 83 · see citing works
Recent insights on astrocyte mechanisms in CNS homeostasis, pathology, and repair
Hart, C. G., & Karimi‐Abdolrezaee, S. (2021) · Journal of Neuroscience Research · doi:10.1002/jnr.24922 · Cited by 85 · see citing works
Exosome/Liposome-like Nanoparticles: New Carriers for CRISPR Genome Editing in Plants
Alghuthaymi, M. A., Ahmad, A., Khan, Z., Khan, S. H., Ahmed, F. K., Faiz, S., Nepovimova, E., Kuča, K., & Abd-Elsalam, K. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147456 · Cited by 83 · see citing works
“Gene knockout YFP Gold nanoparticles [76] Gene knockout H11 Core-shell NPs [77] Gene knockout EGFP Bioreducible lipids [78]”
BackgroundRNA delivery biomaterials for the treatment of genetic and rare diseases
Zhao, W., Hou, X., Vick, O. G., & Dong, Y. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119291 · Cited by 82 · see citing works
Harnessing nanoparticles for the efficient delivery of the CRISPR/Cas9 system
Rahimi, H., Salehiabar, M., Charmi, J., Barsbay, M., Ghaffarlou, M., Razlighi, M. R., Davaran, S., Khalilov, R. I., Sugiyama, M., Nosrati, H., et al. (2020) · Nano Today · doi:10.1016/j.nantod.2020.100895 · Cited by 83 · see citing works
Luo, M., Lee, L. K. C., Peng, B., Choi, C. H. J., Tong, W. Y., & Voelcker, N. H. (2022) · Advanced Science · doi:10.1002/advs.202201740 · Cited by 81 · see citing works
Wang, Y., Wang, X., Xie, R., Burger, J. C., Tong, Y., & Gong, S. (2022) · Advanced Materials · doi:10.1002/adma.202208018 · Cited by 82 · see citing works
Wang, D., Wang, Y., Wang, J., Ma, J.-Y., Liu, B., Tang, A., & Kong, D. (2022) · Chemical Science · doi:10.1039/d1sc06383a · Cited by 81 · see citing works
Controlled CRISPR‐Cas9 Ribonucleoprotein Delivery for Sensitized Photothermal Therapy
Chen, C., Ma, Y., Du, S., Wu, Y., Shen, P., Yan, T., Li, X., Song, Y., Zha, Z., & Han, X. (2021) · Small · doi:10.1002/smll.202101155 · Cited by 80 · see citing works
Targeted nonviral delivery of genome editors in vivo
Tsuchida, C. A., Wasko, K. M., Hamilton, J. R., & Doudna, J. A. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2307796121 · Cited by 79 · see citing works
In vivo locus-specific editing of the neuroepigenome
Yim, Y. Y., Teague, C. D., & Nestler, E. J. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-020-0334-y · Cited by 76 · see citing works
Synthetic multi-layer nanoparticles for CRISPR-Cas9 genome editing
Tang, H., Zhao, X., & Jiang, X. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.03.001 · Cited by 76 · see citing works
Suppression of proteolipid protein rescues Pelizaeus–Merzbacher disease
Elitt, M. S., Barbar, L., Shick, H. E., Powers, B. E., Maeno-Hikichi, Y., Madhavan, M., Allan, K. C., Nawash, B. S., Gevorgyan, A. S., Hung, S., et al. (2020) · Nature · doi:10.1038/s41586-020-2494-3 · Cited by 75 · see citing works
Brain-targeted CRISPR/Cas9 nanomedicine for effective glioblastoma therapy
静香, 前., Jiao, M., Xu, S., Ismail, M., Xie, X., An, Y., Guo, H., Qian, R., Shi, B., & Zheng, M. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.09.046 · Cited by 75 · see citing works
Sun, Y., Xu, X., Chen, L., Chew, W. L., Yuan, P., & Miserez, A. (2023) · ACS Nano · doi:10.1021/acsnano.3c02669 · Cited by 76 · see citing works
In situ self-assembling Au-DNA complexes for targeted cancer bioimaging and inhibition
Wang, M., Chen, Y., Cai, W., Feng, H., Du, T., Liu, W., Jiang, H., Pasquarelli, A., Weizmann, Y., & Wang, X. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1915512116 · Cited by 74 · see citing works
Targeted lipid nanoparticles for RNA therapeutics and immunomodulation in leukocytes
Veiga, N., Diesendruck, Y., & Peer, D. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.04.002 · Cited by 74 · see citing works
Advances in Nanoparticles as Non-Viral Vectors for Efficient Delivery of CRISPR/Cas9
Kim, M., Hwang, Y., Lim, S., Jang, H., & Kim, H. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16091197 · Cited by 75 · see citing works
Sago, C. D., Lokugamage, M. P., Loughrey, D., Lindsay, K. E., Hincapie, R., Krupczak, B. R., Kalathoor, S., Sato, M., Echeverri, E. S., Fitzgerald, J. P., et al. (2022) · Nature Biomedical Engineering · doi:10.1038/s41551-022-00847-9 · Cited by 74 · see citing works
Gene editing therapeutics based on mRNA delivery
Popovitz, J., Sharma, R. K., Hoshyar, R., Kim, B. S., Murthy, N., & Lee, K. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.115026 · Cited by 73 · see citing works
Recent advances in gene therapy for neurodevelopmental disorders with epilepsy
Turner, T. J., Zourray, C., Schorge, S., & Lignani, G. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15168 · Cited by 71 · see citing works
A Duplex CRISPR-Cas9 Ribonucleoprotein Nanomedicine for Colorectal Cancer Gene Therapy
Wan, T. Y., Pan, Q., Liu, C., Guo, J., Li, B., Yan, X., Cheng, Y., & Yuan, P. (2021) · Nano Letters · doi:10.1021/acs.nanolett.1c03708 · Cited by 71 · see citing works
Hazrati, A., Malekpour, K., Soudi, S., & Hashemi, S. M. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113943 · Cited by 73 · see citing works
Natanzi, A. S., Poudineh, M., Karimi, E., Khaledi, A., & Kashani, H. H. (2025) · BMC Medicine · doi:10.1186/s12916-025-04323-4 · Cited by 73 · see citing works
Nanoparticles-mediated CRISPR/Cas9 delivery: Recent advances in cancer treatment
Aghamiri, S., Talaei, S., Ghavidel, A. A., Zandsalimi, F., Masoumi, S., Hafshejani, N. H., & Jajarmi, V. (2020) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2020.101533 · Cited by 69 · see citing works
Cavazza, A., Molina-Estévez, F. J., Reyes, Á. P., Ronco-Díaz, V., Naseem, A., Malenšek, Š., Pečan, P., Santini, A., Heredia, P., Aguilar-González, A., et al. (2025) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2025.102457 · Cited by 70 · see citing works
CRISPR/Cas9 ribonucleoprotein-mediated genome and epigenome editing in mammalian cells
Bloomer, H., Khirallah, J., Li, Y., & Xu, Q. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114087 · Cited by 70 · see citing works
Allemailem, K. S., Alsahli, M. A., Almatroudi, A., Alrumaihi, F., Alkhaleefah, F. K., Rahmani, A. H., & Khan, A. A. (2022) · 癌症：英文版 · doi:10.1002/cac2.12366 · Cited by 69 · see citing works
Tan, E., Wan, T. Y., Pan, Q., Duan, J., Zhang, S., Wang, R., Gao, P., Lv, J., Wang, H., Li, D., et al. (2024) · Science Advances · doi:10.1126/sciadv.adl4336 · Cited by 68 · see citing works
Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection
Tuma, J., Chen, Y.-J., Collins, M. G., Paul, A., Li, J., Han, H., Sharma, R., Murthy, N., & Lee, H. Y. (2023) · Biochemistry · doi:10.1021/acs.biochem.3c00371 · Cited by 65 · see citing works
Nanoengineering in biomedicine: Current development and future perspectives
Jian, W., Hui, D., & Lau, D. (2020) · Nanotechnology Reviews · doi:10.1515/ntrev-2020-0053 · Cited by 65 · see citing works
Non-viral strategies for delivering genome editing enzymes
Li, J., Røise, J. J., He, M., Das, R., & Murthy, N. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.09.004 · Cited by 63 · see citing works
Li, M., Sun, X., Yin, M., Shen, J., & Yan, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065121 · Cited by 62 · see citing works
Delivery technologies for in utero gene therapy
Palanki, R., Peranteau, W. H., & Mitchell, M. J. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.11.002 · Cited by 64 · see citing works
Genome editing reagent delivery in plants
Ghogare, R., Ludwig, Y., Bueno, G. M., Slamet-Loedin, I. H., & Dhingra, A. (2021) · Transgenic Research · doi:10.1007/s11248-021-00239-w · Cited by 61 · see citing works
Xie, R., Wang, X., Wang, Y., Ye, M., Zhao, Y., Yandell, B. S., & Gong, S. (2022) · Advanced Materials · doi:10.1002/adma.202110618 · Cited by 61 · see citing works
- Authors
- Lee, B., Lee, K., Panda, S., Gonzales-Rojas, R., Chong, A., Bugay, V., Park, H. M., Brenner, R., Murthy, N., & Lee, H. Y.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- University of California, Berkeley (US)
- Corresponding author
- Murthy, Niren
- Lee, Hye Young
- Venue
- Nature Biomedical Engineering
- Published
- 2018-06-25
- Volume
- 2
- Issue
- 7
- Pages
- 497-507
- ISSN
- 2157-846X (ISSN-L)
- PMC
- PMC6544395
- OpenAlex
- W2810249184
- Cited by
- 361
- References
- 54
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 36 · 2023: 42 · 2022: 58 · 2021: 56 · 2020: 66 · 2019: 38 · 2018: 15
- FWCI
- 16.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Biomedical Engineering (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI117064)
- National Institute of Biomedical Imaging and Bioengineering (R01EB023776, R01EB020008)
- 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 › Genetics › Virus-based gene therapy research
- Keywords
- CRISPR/Cas9 delivery, non-viral gene delivery, intracranial injection, fragile X syndrome, repetitive behavior, metabotropic glutamate receptor 5, mGluR5, CRISPR/Cas12a, striatum, autism spectrum disorder, astrocytes, microglia, neurons
- MeSH terms
- Animals, Behavior, Animal, Brain, Corpus Striatum, Disease Models, Animal, Fragile X Syndrome, Gold, Humans, Mice, Inbred C57BL, Neurons, Mice, Knockout, Patch-Clamp Techniques, Thy-1 Antigens, Mice, Fragile X Messenger Ribonucleoprotein 1, Nanoparticles, HEK293 Cells, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems, Receptor, Metabotropic Glutamate 5
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
