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How can we use Gene Editing to protect or cure us from viral infections?

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Manel Lladó Santaeularia
Manel Lladó Santaeularia Dec 06, 2020

[1]Ernst, M.P.T., et al., Ready for Repair? Gene Editing Enters the Clinic for the Treatment of Human Disease. Mol Ther Methods Clin Dev, 2020. 18: p. 532-557.

[2]Lee, C., CRISPR/Cas9-Based Antiviral Strategy: Current Status and the Potential Challenge. Molecules, 2019. 24(7).

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Using Recombinase to achieve targeted HIV excision

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Antonio Carusillo
Antonio Carusillo Dec 27, 2020

[1]Falkenhagen A, Joshi S. Genetic Strategies for HIV Treatment and Prevention. Mol Ther Nucleic Acids. 2018;13:514-533. doi:10.1016/j.omtn.2018.09.018

[2]Alkhatib G. The biology of CCR5 and CXCR4. Curr Opin HIV AIDS. 2009;4(2):96-103. doi:10.1097/COH.0b013e328324bbec

[3]Battistini, A. & Sgarbanti, M. HIV-1 latency: an update of molecular mechanisms and therapeutic strategies. Viruses 6, 1715–1758 (2014).

[4]Verheyen J, Thielen A, Lübke N, Dirks M, Widera M, Dittmer U, Kordelas L, Däumer M, de Jong DCM, Wensing AMJ, Kaiser R, Nijhuis M, Esser S. Rapid Rebound of a Preexisting CXCR4-tropic Human Immunodeficiency Virus Variant After Allogeneic Transplantation With CCR5 Δ32 Homozygous Stem Cells. Clin Infect Dis. 2019 Feb 1;68(4):684-687. doi: 10.1093/cid/ciy565. PMID: 30020413.

[5]Yu S, Yao Y, Xiao H, Li J, Liu Q, Yang Y, Adah D, Lu J, Zhao S, Qin L, Chen X. Simultaneous Knockout of CXCR4 and CCR5 Genes in CD4+ T Cells via CRISPR/Cas9 Confers Resistance to Both X4- and R5-Tropic Human Immunodeficiency Virus Type 1 Infection. Hum Gene Ther. 2018 Jan;29(1):51-67. doi: 10.1089/hum.2017.032. Epub 2017 Jun 9. PMID: 28599597.

[6]Lekomtsev, S., Aligianni, S., Lapao, A. et al. Efficient generation and reversion of chromosomal translocations using CRISPR/Cas technology. BMC Genomics 17, 739 (2016). https://doi.org/10.1186/s12864-016-3084-5

[7]Karpinski, J., Hauber, I., Chemnitz, J. et al. Directed evolution of a recombinase that excises the provirus of most HIV-1 primary isolates with high specificity. Nat Biotechnol 34, 401–409 (2016). https://doi.org/10.1038/nbt.3467

[8]Crudele, J.M., Chamberlain, J.S. Cas9 immunity creates challenges for CRISPR gene editing therapies. Nat Commun 9, 3497 (2018). https://doi.org/10.1038/s41467-018-05843-9

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Manel Lladó Santaeularia
Manel Lladó Santaeularia17 days ago
Hi Antonio! Great contribution! I find recombinases to be a very interesting and often forgotten tool, although as you mentioned, design is not easy and a lot of protein evolution efforts may be needed to target them to a particular sequence. I was wondering wether it could be possible to exploit Cas9 RNA-based specificity and design flexibility together with the specific recombination ability of recombinases. And this is indeed possible, and was actually done all the way back in 2016 , although with low efficiency. However, it was reported last year that RNA-Guided Recombinase-Cas9 fusion proteins can target genomic DNA achieving both deletions and integrations. This was achieved by targeting the recombinase-Cas9 to two target sites with PAM-distal orientations (meaning the first PAM is in the 5' strand and the second one in the 3') and having the two hyperactive recombinase domains be in the middle so they can recognize each other and excise the DNA fragment between the two targeted sites. [1]

Although this kind of strategy is still in relatively early development, I'm sure if they achieve high efficiencies we will definitely see them being applied to viral infections.

1. Standage-Beier K, Brookhouser N, Balachandran P, Zhang Q, Brafman DA, Wang X. RNA-Guided Recombinase-Cas9 Fusion Targets Genomic DNA Deletion and Integration. CRISPR J. 2019 Aug;2(4):209-222. doi: 10.1089/crispr.2019.0013. PMID: 31436506; PMCID: PMC6707420.

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