Safety and Efficacy Clinical Trials for SYL1001, a Novel Short Interfering RNA for the Treatment of Dry Eye Disease

Benítez-del-Castillo, J.M.; Moreno-Montañés, Javier; Jiménez-Alfaro, Ignacio; Muñoz‐Negrete, Francisco J.; Turman, Krista; Palumaa, Kadi; Sádaba, Belén; González, Marı́a Victoria; Ruz, Veronica; Vargas, Beatriz; Pañeda, Covadonga; Martínez, Tamara; Bleau, Anne Marie; Jiménez, Ana I.

doi:10.1167/iovs.16-20303

Cited by 79 publications

(54 citation statements)

References 24 publications

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“…In a large, placebo‐controlled clinical trial, SYL1001 demonstrated significant improvements in visual analogue scale scores and excellent tolerability (Benitez‐Del‐Castillo et al. ).…”

Section: Treatment Optionsmentioning

confidence: 99%

Role of corneal nerves in ocular surface homeostasis and disease

Labétoulle

Baudouin

Calonge

et al. 2018

Acta Ophthalmologica

155

102

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Corneal nerves are key components of the physiological system that controls ocular surface homeostasis. The cornea is primarily innervated by the ophthalmic branch of the trigeminal nerves (cranial nerve V), which distend bilaterally from the pons. The nasociliary branch (afferent) of the ophthalmic nerve is sensory for cornea, eyelid and conjunctiva. These nerve fibres play a role in sensing temperature, chemical and mechanical stimuli, and pain, whereas, branches of the facial nerve (cranial nerve VII) contain motor nerves that control blinking and autonomic (sympathetic and a paucity of parasympathetic) fibres that stimulate tear production and secretion via feedback loops between the ocular surface, lacrimal glands and brain. Disruption of these nerves with interruption of neural feedback loops between the ocular surface and lacrimal glands can lead to corneal diseases such as dry eye disease (DED) and neurotrophic keratopathy (NK). Inversely, hypersensitivity of the nerve fibres and/or dysregulation of pain-controlling nervous centres may lead to neuropathic pain. Recently, medications that specifically target regeneration of corneal nerves have started to become available - and considering the high prevalence of diseases associated with corneal nerve dysfunction, these agents promise to fulfil a hitherto important unmet need. In this review, we explore the physiology of corneal nerves, the pathology of corneal nerve diseases and how these relate to neuropathic pain, NK and DED. We also discuss what novel treatments may be useful against diseases involving corneal nerves.

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Section: Treatment Optionsmentioning

confidence: 99%

Role of corneal nerves in ocular surface homeostasis and disease

Labétoulle

Baudouin

Calonge

et al. 2018

Acta Ophthalmologica

155

102

View full text Add to dashboard Cite

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“…* P < 0.05 compared with control, unless specified. [28,29]. It is possible to apply silencing SPARC in vivo with a similar technique, and the in vivo application of silencing SPARC in patients receiving filtering surgery is an important researching field of our future study.…”

Section: Discussionmentioning

confidence: 99%

SPARC Levels Modulate the Capacity of Mitomycin to Inhibit the Proliferation of Human Tenon’s Capsule Fibroblasts

Guo

Zhou

et al. 2020

Journal of Ophthalmology

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Purpose. To evaluate the role of SPARC in the antiproliferation effect of MMC on human Tenon’s fibroblasts (HTF). Method. Sixteen PACG patients aged 59 ± 10 years (31–72 years), including 6 males and 10 females, were recruited. Tenon tissue was harvested during filtering surgery. Cell density was evaluated after MMC application with different concentrations and application times, by which the optimized MMC application modality was determined. MMC, si-SPARC, or SPARC protein was used when needed to evaluate the cell densities under different conditions, by which the role of SPARC in MMC-mediated antifibrotic process was identified. Results. Considering that the cell densities, as well as SPARC expression on mRNA and protein levels, are relatively stable when the MMC concentration is higher than 0.02% and exposure time longer than 90 s, we chose the MMC application pattern with 0.02% and 90 s as an optimized pattern for the downstream work. Compared to control, the si-SPARC and MMC downregulated the SPARC protein by 91% (P<0.01) and 65% (P<0.01) and mRNA by 96% (P<0.01) and 64% (P<0.01), respectively. MMC decreases the cell densities by 53.50% compared to control. si-SPARC + MMC dramatically deceased the cell density no matter compared to the control group (P<0.01) or MMC group (P<0.01); correspondingly, the relative collagen gel area in the MMC + si-SPARC group was higher than that in the MMC group or si-SPARC group (P<0.05). The reactive oxygen species expression in the MMC + si-SPARC group is higher than that in the MMC group (P<0.05). Conclusion. This study demonstrates that in HTF, (1) MMC downregulates the expression of SPARC in protein and mRNA levels; (2) SPARC depletion has synergistic effect on the antifibrotic effect of MMC; and (3) reactive oxygen species are the possible mediator in the antifibrotic effect of MMC and si-SPARC.

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“…QPI‐1002 and QPI‐1007 were developed by Quark Pharmaceuticals, for the treatment of delayed graft function (phase 3) and acute kidney injury (phase 2), as well as nonarteritic anterior ischemic optic neuropathy (phase 3) and acute primary angle closure glaucoma (phase 2), by targeting p53 and caspase 2, respectively. SYL1001 was developed by Sylentis for the treatment of ocular pain and dry eye syndrome, by targeting transient receptor potential cation channel subfamily V member 1 (TRPV1) …”

Section: Performance Of Sirna Therapy In Clinical Trailsmentioning

confidence: 99%

Clinical advances of siRNA therapeutics

Weng

Xia

et al. 2019

The Journal of Gene Medicine

138

110

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Small interfering RNA (siRNA) enables efficient target gene silencing by employing a RNA interference (RNAi) mechanism, which can compromise gene expression and regulate gene activity by cleaving mRNA or repressing its translation. Twenty years after the discovery of RNAi in 1998, ONPATTRO™ (patisiran) (Alnylam Pharmaceuticals, Inc.), a lipid formulated siRNA modality, was approved for the first time by United States Food and Drug Administration and the European Commission in 2018. With this milestone achievement, siRNA therapeutics will soar in the coming years. Here, we review the discovery and the mechanisms of RNAi, briefly describe the delivery technologies of siRNA, and summarize recent clinical advances of siRNA therapeutics.

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Safety and Efficacy Clinical Trials for SYL1001, a Novel Short Interfering RNA for the Treatment of Dry Eye Disease

Abstract: These trials achieved their primary endpoints of identifying the most effective dose of SYL1001 (1.125%). SYL1001 showed a large safety margin and may provide novel therapeutic opportunity for the relief of dry eye. (ClinicalTrials.gov numbers, NCT01438281, NCT01776658, and NCT02455999.).

Cited by 79 publications

References 24 publications

Role of corneal nerves in ocular surface homeostasis and disease

Role of corneal nerves in ocular surface homeostasis and disease

SPARC Levels Modulate the Capacity of Mitomycin to Inhibit the Proliferation of Human Tenon’s Capsule Fibroblasts

Clinical advances of siRNA therapeutics

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