Meganuclease targeting HSV-1 protects against herpetic keratitis: Application to corneal transplants

Chapellier, Benoît; Guindolet, Damien; Pereira, Daniel de Souza; Galetto, Román; Sahel, José‐Alain; Labétoulle, Marc; Gabison, Éric

doi:10.1016/j.omtn.2022.11.006

Cited by 8 publications

(4 citation statements)

References 30 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, destabilizing the HUSH-SETDB1-MORC2 entity might be considered as a complementary approach to proposed therapies designed to modify viral genomes to prevent their reactivation. As an example, viral genomes editing using meganucleases or CRISPR/Cas9 technologies has been proposed to eliminate latent HSV reservoirs [52][53][54][55] . Provoking sub-reactivation of HSV-1 by inactivating the HUSH-SETDB1-MORC2 entity could then potentiate the use of these technologies, provided that it does not induce global epigenetic modifications that would put a threat on cellular defense mechanisms.…”

Section: Discussionmentioning

confidence: 99%

The HUSH-SETDB1-MORC2 epigenetic repressor complex restricts herpesvirus infection in association with PML nuclear bodies

Roubille

Juillard

Escure

et al. 2023

Preprint

View full text Add to dashboard Cite

The establishment of latent herpes simplex virus 1 (HSV-1) infection is controlled by promyelocytic leukemia nuclear bodies (PML NBs). Viral genomes are recruited to PML NBs structures and chromatinized by repressive H3.3K9me3 modified H3.3 histone variant to form viral DNA-containing PML-NBs (vDCP NBs). Exactly how this occurs is unclear. Here we identify an essential role for the HUSH complex and its SETDB1 and MORC2 effectors in the establishment and maintenance of latent herpes simplex virus 1 (HSV-1) infection. We show that the formation of repressive heterochromatin is dependent on HUSH, SETDB1 and MORC2 in vDCP NBs, and depletion of any of these components prior to viral infection decreases H3K9me3 levels over latent/quiescent HSV-1 genomes. Once latency is established, depletion of HUSH, SETDB1, or MORC2 by shRNAs or the HIV-2 Vpx protein, induces the reactivation of HSV-1 in infected primary human fibroblasts as well as human induced pluripotent stem cell-derived sensory neurons (hiPSDN). Our data demonstrate the potent antiviral restriction activity of the HUSH/SETDB1/ MORC2 complex to a non-integrated human herpesvirus, its close association with PML NBs, and introduces a new target for anti-herpesvirus therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

The HUSH-SETDB1-MORC2 epigenetic repressor complex restricts herpesvirus infection in association with PML nuclear bodies

Roubille

Juillard

Escure

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Gene therapy (using an adenovirus type-2 vector) via meganuclease delivery to HSV-1 infected rabbit cornea transplantation models led to reduced HSV expression and attenuated immune responses[ 376 ]. Metabolic reprogramming via intraperitoneal metformin in mice infected with ocular HSV led to reduced expression of HSK lesions; with marked limitation of CNS complications induced by attempted metabolic therapy with 2-deoxy-d-glucose[ 377 ].…”

Section: Novel Therapeutic Approaches For Herpes Simplex Keratitis: C...mentioning

confidence: 99%

Herpes simplex keratitis: A brief clinical overview

Musa,

Enaholo,

Aluyi-Osa

et al. 2024

World J Virol

View full text Add to dashboard Cite

The aim of our minireview is to provide a brief overview of the diagnosis, clinical aspects, treatment options, management, and current literature available regarding herpes simplex keratitis (HSK). This type of corneal viral infection is caused by the herpes simplex virus (HSV), which can affect several tissues, including the cornea. One significant aspect of HSK is its potential to cause recurrent episodes of inflammation and damage to the cornea. After the initial infection, the HSV can establish a latent infection in the trigeminal ganglion, a nerve cluster near the eye. The virus may remain dormant for extended periods. Periodic reactivation of the virus can occur, leading to recurrent episodes of HSK. Factors triggering reactivation include stress, illness, immunosuppression, or trauma. Recurrent episodes can manifest in different clinical patterns, ranging from mild epithelial involvement to more severe stromal or endothelial disease. The severity and frequency of recurrences vary among individuals. Severe cases of HSK, especially those involving the stroma and leading to scarring, can result in vision impairment or even blindness in extreme cases. The cornea's clarity is crucial for good vision, and scarring can compromise this, potentially leading to visual impairment. The management of HSK involves not only treating acute episodes but also implementing long-term strategies to prevent recurrences and attempt repairs of corneal nerve endings via neurotization. Antiviral medications, such as oral Acyclovir or topical Ganciclovir, may be prescribed for prophylaxis. The immune response to the virus can contribute to corneal damage. Inflammation, caused by the body's attempt to control the infection, may inadvertently harm the corneal tissues. Clinicians should be informed about triggers and advised on measures to minimize the risk of reactivation. In summary, the recurrent nature of HSK underscores the importance of both acute and long-term management strategies to preserve corneal health and maintain optimal visual function.

show abstract

“…Although decreasing infection and growing survival is recommended in treating herpetic keratitis, it does no longer honestly therapy the disease. For this reason, in latest years, the center of attention has shifted to focused on the HSV-1 genome for degradation the use of ribozymes [245], AONs [246], siRNA [247], aptamers [248], and homing endonucleases [249].…”

Section: Herpetic Keratitismentioning

confidence: 99%

Ocular Gene Therapy: Literature Review

Naser,

M. Nasr,

Shehata

2023

IJPSAT

View full text Add to dashboard Cite

This literature offers complete information about the advances in gene treatment in the of the eye, inclusive of cornea, conjunctiva, lacrimal gland, and trabecular meshwork. We talked about gene transport systems, collectively with viral and non-viral vectors as exact as gene modifying techniques, generally CRISPR-Cas9, and epigenetic treatments, consisting of antisense and siRNA therapeutics. We moreover furnish a specific assessment of gene treatment has been examined with corresponding outcomes. Disease stipulations embody corneal and conjunctival fibrosis and scarring, corneal epithelial wound healing, corneal graft survival, corneal neovascularization, genetic corneal dystrophies, herpetic keratitis, glaucoma, dry eye disease, and specific ocular surface diseases. Although most of the analyzed consequences on the use and validity of gene treatment at the ocular surface have been offered in vitro or the utilization of animal models, we moreover talked about the on hand human studies. Gene treatment methods are nowadays viewed very promising as rising future remedies of a variety of diseases, and this area is unexpectedly expanding.

show abstract

Meganuclease targeting HSV-1 protects against herpetic keratitis: Application to corneal transplants

Cited by 8 publications

References 30 publications

The HUSH-SETDB1-MORC2 epigenetic repressor complex restricts herpesvirus infection in association with PML nuclear bodies

The HUSH-SETDB1-MORC2 epigenetic repressor complex restricts herpesvirus infection in association with PML nuclear bodies

Herpes simplex keratitis: A brief clinical overview

Ocular Gene Therapy: Literature Review

Contact Info

Product

Resources

About