Targeting corneal inflammation by gene therapy: Emerging strategies for keratitis

Torrecilla, Josune; Pozo-Rodríguez, Ana del; Vicente-Pascual, Mónica; Solinís, Maria Ángelés; Rodríguez-Gascón, Alicia

doi:10.1016/j.exer.2018.07.006

Cited by 27 publications

(26 citation statements)

References 143 publications

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“…Retroviruses, lentiviruses, adenoviruses, and adeno-associated viruses have been used for transfecting the cornea. However, the induction of the immune response and inflammation limits the application of viral vectors to inflammatory diseases, including cornea inflammation, even considering its relative immune privilege [ 1 ]. Moreover, they have been frequently administered by invasive methods such as intrastromal, intralimbal, intracameral, or after removing the corneal epithelium [ 30 , 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…The cornea, a transparent anatomical structure in the anterior segment of the eye, plays a significant role in sight by refracting light to focus a visual image. This tissue can be injured by several factors (infections, dry eye, disorders of the eyelids, physical and chemical damage, and a wide variety of underlying diseases) causing corneal inflammation or keratitis [ 1 ]. Common symptoms and signs of keratitis include eye pain, blurred vision, photophobia, tearing, and eye redness, reaching visual impairment and blindness when chronic inflammation results in tissue destruction [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…A significant number of studies have evaluated the potential of gene therapy to deliver specific anti-inflammatory factors to treat keratitis. Interleukin-10 (IL-10) is a potent immunomodulatory cytokine that interacts with antigen presenting cells inhibiting the production of proinflammatory cytokines such as IL-1, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha [ 1 , 6 , 7 , 8 , 9 , 10 ]. IL-10 gene delivery has been proposed to induce a sustained synthesis of the protein de novo in corneal cells, providing a long-term anti-inflammatory effect [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Topical Administration of SLN-Based Gene Therapy for the Treatment of Corneal Inflammation by De Novo IL-10 Production

et al. 2020

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One of the main challenges in gene therapy is the issue of delivery, and it is especially relevant for the success of gene therapy in the cornea. In the present work, eye drops containing biocompatible non-viral vectors based on solid lipid nanoparticles (SLNs) as gene delivery systems to induce the expression of interleukin 10 (IL-10) were designed to address the treatment of corneal inflammation. Two kinds of SLNs combined with different ligands (protamine, dextran, or hyaluronic acid (HA)) and formulated with polyvinyl alcohol (PVA) were prepared. SLN-based vectors were characterized in terms of size, adhesiveness, viscosity, and pH, before topical administration to wild type and IL-10 knock out (KO) mice. The formulations showed a homogenous particle size below 400 nm and a positive surface charge to favor bioadhesion; the incorporation of PVA improved the corneal penetration. After three days of treatment by topical instillation, SLN-based vectors mainly transfected corneal epithelial cells, HA-formulations being the most effective ones. IL-10 was capable of reaching even the endothelial layer. Corneal sections showed no histological change and formulations seemed to be well tolerated after repeated topical administration. These promising results highlight the possible contribution of non-viral gene augmentation therapy to the future clinical approach of corneal gene therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Topical Administration of SLN-Based Gene Therapy for the Treatment of Corneal Inflammation by De Novo IL-10 Production

et al. 2020

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“…For example, the ability of adeno-associated viruses (AAVs) to deliver repair genes to the corneal epithelium or endothelium has been verified in animal experiments, although the uncertainty of inflammatory response limits the development of this technique ( Lu et al, 2016 ). CRISPR-based gene editing technology could also be used to specifically modify target genes ( Chen & Niu, 2019 ; Ma et al, 2018 ; Sun et al, 2019 ); however, this method is still in its infancy in regard to the treatment of ocular surface diseases ( Torrecilla et al, 2018 ). Encouragingly, the CRISPR/Cas9 technique has been shown to target gRNAs to specific viral genes, effectively eliminating HSV-1-induced corneal inflammation ( van Diemen et al, 2016 ).…”

Section: Targeting Cilia For Corneal Disease Treatmentmentioning

confidence: 99%

Primary cilia in corneal development and disease

Song¹,

Zhou

2020

Zoological Research

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As a transparent avascular tissue located at the front of the eyeball, the cornea is an important barrier to external damage. Both epithelial and endothelial cells of the cornea harbor primary cilia, which sense changes in the external environment and regulate intracellular signaling pathways. Accumulating evidence suggests that the primary cilium regulates corneal development in several ways, including participation in corneal epithelial stratification and maintenance of corneal endothelial cell morphology. In addition, the primary cilium has been implicated in the pathogenesis of several corneal diseases. In this review, we discuss recent findings that demonstrate the critical role of the primary cilium in corneal development. We also discuss the link between ciliary dysfunction and corneal diseases, which suggests that the primary cilium could be targeted to treat these diseases.

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“…Anti-inflammatory treatment is the primary therapy for the early treatment of paraquat poisoning (5). A number of genes that are differentially expressed during the occurrence and development of inflammation are candidate targets for gene therapy, including some microRNAs (miRNAs/miRs) (10). A recent study reported that miR-146a can regulate the occurrence and immune response of lung injury induced by paraquat poisoning, and that interleukin (IL)-6 is involved in the regulation of this process (11).…”

Section: Introductionmentioning

confidence: 99%

Clinical significance of serum levels of microRNA‑27a and its correlation with interleukin‑10 in patients with multiple organ dysfunction syndrome caused by acute paraquat poisoning

Dai

Zhang

et al. 2020

Exp Ther Med

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The aims of the present study were to examine the clinical significance of serum microRNA-27a (miR-27a) levels in patients with multiple organ dysfunction syndrome (MODS) caused by acute paraquat poisoning and to investigate the correlation between miR-27a and interleukin (IL)-10. A total of 82 patients with MODS induced by acute paraquat poisoning and 88 healthy controls were recruited in the present study. Reverse transcription-quantitative PCR was used to measure serum miR-27a expression levels in patients with MODS and the control group. IL-10 serum levels were determined using ELISA. Decreased serum miR-27a level and increased IL-10 expression levels were detected in patients with paraquat poisoning compared with healthy controls (P<0.001). A moderately negative correlation was identified between the serum expression levels of miR-27a and IL-10 (r=-0.5225; P<0.001). miR-27a expression level was found to be associated with blood urea nitrogen, partial pressure of carbon dioxide, arterial blood lactic acid, and the acute physiology and chronic health evaluation II score (APACHE II; P<0.05). The area under the curve for miR-27a was 0.946, with a sensitivity of 86.6% and specificity of 87.5% at a cutoff value of 2.10. The non-survival patient group had lower miR-27a expression levels compared with the survival group (P<0.01). Multivariate Cox regression analyses suggested miR-27a expression level and APACHE II score were independent prognostic factors for 30-day mortality (P<0.01). The present results suggested that serum miR-27a level may be a potential novel diagnostic and prognostic factor for MODS caused by paraquat poisoning. Collectively, miR-27a may be involved in the process of MODS induced by paraquat poisoning by regulating the inflammatory response.

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Targeting corneal inflammation by gene therapy: Emerging strategies for keratitis

Cited by 27 publications

References 143 publications

Topical Administration of SLN-Based Gene Therapy for the Treatment of Corneal Inflammation by De Novo IL-10 Production

Topical Administration of SLN-Based Gene Therapy for the Treatment of Corneal Inflammation by De Novo IL-10 Production

Primary cilia in corneal development and disease

Clinical significance of serum levels of microRNA‑27a and its correlation with interleukin‑10 in patients with multiple organ dysfunction syndrome caused by acute paraquat poisoning

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