SYL040012, a siRNA for the treatment of glaucoma

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Abstract

Purpose

SYL040012 is a siRNA under developed for the treatment of glaucoma and increased intraocular pressure (IOP). siRNAs are small double stranded RNAs that regulate protein expression at transcription level using the endogenous RNA interference machinery. Therapeutically siRNAs are attractive due to their specificity, potency and ability to silence targets that are not addressable by small molecules. SYL040012 targets ADRB2, a well-known target for glaucoma.

Methods

Silencing activity of SYL040012 was validated in cell lines and IOP lowering efficacy was studied in rabbit. Silencing activity was assessed by extracting total RNA from cells or animal tissues and analyzed by real time-PCR. IOP was measured using applanation tonometry. Tissue and plasma exposure was evaluated following a single instillation to rabbits using a non-denaturing Anion Exchange HPLC combined with fluorescence detection. 28-day regulatory toxicology studies were performed in cynomolgus monkeys following a daily ocular instillation of one of three doses of SYL040012 or vehicle. Phase I clinical trials were performed in healthy volunteers or individuals with increased IOP that received either a single dose or seven repeated administrations of SYL040012.

Results

SYL040012 reaches structures of the eye relevant to the treatment of glaucoma when administered in eye drops; but is only detected in systemic circulation and non-ocular tissues at trace levels. Presence of this compound in the ciliary body it results in specific down-regulation of the target gene and reduction in IOP in animal models. Preclinical and clinical studies show that SYL040012 is well tolerated both systemically and locally.

Conclusion

In summary, SYL040012 is a promising candidate for the treatment of increased intraocular pressure associated to glaucoma.

Conclusion

Commercial interest

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