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Veronica Ruz, Victoria Gonzalez, Carmen Martinez-Garcia, Covadonga Pañeda, Ana Isabel Jiménez; SYL1001, a new treatment based on RNAi for the treatment of ocular pain.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3673.
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SYL1001 is small interfering RNA targeting transient receptor potential cation channel subfamily V member 1 (TRPV1). The compound, administered in eye drops, is undergoing clinical development for the treatment of ocular pain. SYL1001 decreases TRPV1 in animal models and reduces pain related behavior in an animal model of capsaicin induced eye pain.
Biodistribution studies for SYL1001 and its active metabolite were performed in New Zealand rabbits. Five minutes after administration the ocular structures were harvested: cornea, conjunctiva and lachrymal gland. The trigeminal/semilunar ganglion was collected to assess if the compound was able to reach the neurons innervating the cornea. Lung, liver, kidneys and plasma were collected to assess systemic exposure. Phase 1A in healthy subjects was completed in 2011 and a phase 1/2 clinical trial is currently ongoing. SYL1001_I (NCT01438281) was an open-label, controlled, single-centre, phase 1 study that assessed safety of SYL1001 in 30 healthy subjects. SYL1001_II (NTC1776658) is a double-masked, controlled, multi-center, phase 1/2 study that studies safety and effect of SYL1001 in 60 patients with ocular pain.
Results of the biodistribution studies show that SYL1001 and its active metabolite are present in cornea, conjunctiva, lachrymal gland and trigeminal ganglion; structures were SYL1001 is believed to exert its action. SYL1001 was detected in plasma and the active metabolite of SYL1001 was not present in plasma or systemic organs. TRPV1 protein is expressed in different eye cells from rabbit and human eyes, particularly active in Ca2+ exchange as well as in cells with significant water transport activity. Clinical trials showed that local tolerance was excellent. No serious adverse or modifications of the ocular surface or iris were detected. The analytical results at final examination did not show differences from those observed during selection. Pharmacokinetic results indicated that no levels of siRNAs were detected above in any of the subjects.
Preclinical and clinical development of SYL1001 indicates that the compound is very well tolerated both locally and systemically. SYL1001 was not present in any of the blood samples collected in humans after either a single or repeated dosing schedule; the absence of the compound from systemic circulation indicates that the action of SYL1001 is most likely localized.
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