Inhibition of HSV-1 Replication by Gene Editing Strategy

Roehm, Pamela C.; Shekarabi, Masoud; Wollebo, Hassen S.; Bellizzi, Anna; He, Lifan; Salkind, Julian; Khalili, Kamel

doi:10.1038/srep23146

Cited by 125 publications

(117 citation statements)

References 43 publications

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“…First, we demonstrated the introduction of endonuclease-induced mutations in latent HSV genomes in neurons, the biologically relevant cell type. Previously, we and others showed that HSV infection is inhibited in the presence of HSV-specific endonucleases in vitro (12, 13, 25). We further demonstrated in vitro that HSV-specific HEs could mediate mutagenesis of latent HSV and limit subsequent reactivation (13).…”

Section: Discussionmentioning

confidence: 98%

“…We further demonstrated in vitro that HSV-specific HEs could mediate mutagenesis of latent HSV and limit subsequent reactivation (13). However, none of these previous studies were done in neuronal cells (12, 13, 25), and the demonstration that endonucleases can also mutate HSV in sensory neurons, the relevant cell type for HSV latency, provides support for evaluating this approach in vivo.…”

Section: Discussionmentioning

confidence: 99%

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In vivo disruption of latent HSV by designer endonuclease therapy

Aubert¹,

Madden²,

Loprieno³

et al. 2016

JCI Insight

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A large portion of the global population carries latent herpes simplex virus (HSV), which can periodically reactivate, resulting in asymptomatic shedding or formation of ulcerative lesions. Current anti-HSV drugs do not eliminate latent virus from sensory neurons where HSV resides, and therefore do not eliminate the risk of transmission or recurrent disease. Here, we report the ability of HSV-specific endonucleases to induce mutations of essential HSV genes both in cultured neurons and in latently infected mice. In neurons, viral genomes are susceptible to endonuclease-mediated mutagenesis, regardless of the time of treatment after HSV infection, suggesting that both HSV lytic and latent forms can be targeted. Mutagenesis frequency after endonuclease exposure can be increased nearly 2-fold by treatment with a histone deacetylase (HDAC) inhibitor. Using a mouse model of latent HSV infection, we demonstrate that a targeted endonuclease can be delivered to viral latency sites via an adeno-associated virus (AAV) vector, where it is able to induce mutation of latent HSV genomes. These data provide the first proof-of-principle to our knowledge for the use of a targeted endonuclease as an antiviral agent to treat an established latent viral infection in vivo.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

In vivo disruption of latent HSV by designer endonuclease therapy

Aubert¹,

Madden²,

Loprieno³

et al. 2016

JCI Insight

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“…However in rare cases, HSV-1 can replicate in the central nervous system causing encephalitis. We and several other laboratories applied CRISPR/Cas9 to HSV-1 (Roehm et al, 2016; van Diemen et al, 2016; Li et al, 2017). We found that CRISPR/Cas9 introduced InDels into the HSV-1 ICP0 gene reducing viral infectivity in human cell cultures and protecting them against HSV-1 infection.…”

Section: Recent Applications Of Crisprmentioning

confidence: 99%

“…We found that CRISPR/Cas9 introduced InDels into the HSV-1 ICP0 gene reducing viral infectivity in human cell cultures and protecting them against HSV-1 infection. CRISPR targeting ICP0 plus the ICP4 or ICP27 completely abrogated HSV-1 infection indicating that CRISPR/Cas9 has the potential to be developed as a novel and specific therapeutic and prophylactic tool for HSV-1 disease (Roehm et al, 2016). …”

Section: Recent Applications Of Crisprmentioning

confidence: 99%

CRISPR Editing Technology in Biological and Biomedical Investigation

White

Kaminski

Young

et al. 2017

J of Cellular Biochemistry

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The CRISPR or clustered regularly interspaced short palindromic repeats system is currently the most advanced approach to genome editing and is notable for providing an unprecedented degree of specificity, effectiveness and versatility in genetic manipulation. CRISPR evolved as a prokaryotic immune system to confer provide an acquired immunity and resistance to foreign genetic elements such as bacteriophages. It has recently been developed into a tool for the specific targeting of nucleotide sequences within complex eukaryotic genomes for the purpose of genetic manipulation. The power of CRISPR lies in its simplicity and ease of use, its flexibility to be targeted to any given nucleotide sequence by the choice of an easily synthesized guide RNA, and its ready ability to continue to undergo technical improvements. Applications for CRISPR are numerous including creation of novel transgenic cell animals for research, high-throughput screening of gene function, potential clinical gene therapy and nongene-editing approaches such as modulating gene activity and fluorescent tagging. In this prospect article, we will describe the salient features of the CRISPR system with an emphasis on important drawbacks and considerations with respect to eliminating off-target events and obtaining efficient CRISPR delivery. We will discuss recent technical developments to the system and we will illustrate some of the most recent applications with an emphasis on approaches to eliminate human viruses including HIV-1, JCV and HSV-1 and prospects for the future.

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“…CRISPR/Cas9 was efficiently used to cleave the genome of DNA viruses such as Epstein-Barr virus in human cells and to target herpesvirus genomes in herpesvirus induced diseases such as lymphomas and adenocarcinomas [62][63][64][65][66][67]. The RNAtargeting CRISPR/C2c2 system, which is guided by a single crRNA and has ribonuclease function, could be designed to knock down specific mRNA or cleave the single-stranded viral RNA that carries complementary protospacers, establishing CRISPR/C2c2 system as a novel RNA-targeting strategy [68,69].…”

Section: Possible Therapeutic Applicationsmentioning

confidence: 99%

CRISPR/Cas9-Mediated Genome Nano-Surgery: An Update

Mokbel¹,

Mokbel²

2017

Biochem Mol biol J

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Recent advances in sequencing methods have prompted an upsurge in research into the modification of diseaseassociated genes or genes involved in drug resistance. In the early days of genome-editing, immunogenic and difficult to deliver tools with high off-target effects such as Zinc Finger Nucleases (ZFNs) and Transcription activatorlike effector nucleases (TALENs) proteins were used. This was followed by the discovery of the Clustered Regularly Interspaced Short Palindromic Repeat s, CRISPR/Cas9 system. This "self-non-self-discriminatory" natural defence mechanism in bacteria and archaea identifies and degrades extrachromosomal genomes or foreign genetic elements to prevent them from integrating into the prokaryotic genomes. Unlike traditional gene therapies that can merely insert a gene in a random pattern, the inexpensive and expedient CRISPR/ Cas9 system was harnessed by scientists to precisely cut, add or manipulate multiple DNA sequences at specific sites. This review will focus on the most recent studies in genome-editing by giving an overview of the past and modern methods in this field with an emphasis on the bacterial adaptive immune system called CRISPR/Cas9. This article will also analyze the applications of CRISPR/ Cas9 in rewriting the human genome in clinical and research settings and its potential future therapeutic applications. In addition, we shall consider the technical complexities which need to be overcome for the safe and effective delivery of this novel therapy and how the ethical concerns associated with this revolutionary genome engineering technique have constrained research in germ-line genome-editing. Furthermore, we shall highlight the role of scientific regulatory committees in evaluating and assessing safety issues such as potential complications before translating this proof-of-concept evidential approach to clinical reality. More research is required to explore the risk of hazardous genome edits and to fine-tune and improve this novel therapeutic system. Although the inexpensive and easy to use CRISPR/ Cas9 platform paves new ways for precise genome editing, clinical application is still at an early stage.

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Inhibition of HSV-1 Replication by Gene Editing Strategy

Cited by 125 publications

References 43 publications

In vivo disruption of latent HSV by designer endonuclease therapy

In vivo disruption of latent HSV by designer endonuclease therapy

CRISPR Editing Technology in Biological and Biomedical Investigation

CRISPR/Cas9-Mediated Genome Nano-Surgery: An Update

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