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SILENCING$BETA2$ADRENERGIC$RECEPTORS…$$

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It! is! inevitable! to! compare! the! results! presented! here! with! the! ones!

obtained! with! commercial! antiglaucomatous! drugs.! Commercial! compounds! such!
as!Xalatan,!Trusopt!or!Timoftol!were!capable!of!reducing!IOP!in!our!experimental!
models! although! their! effects! were! significantly! shorter! in! terms! of! timeYeffect!
than! the! ones! obtained! with! the! siRNA! tested! here.! While! the! commercial!
compounds! reduced! IOP! for! a! few! hours,! the! carbonic! anhydrase! siRNA! effect!
lasted! for! several! days.! This! is! a! clear! demonstration! of! the! differences! in! the!
molecular! mechanism! of! action! of! RNAi! silencing! sequences! compared! to! existing!
drugs.!When!RNAi!sequences!are!topically!applied!there!is!a!delay!until!the!effect!is!
observed! in! comparison! with! to! the! commercially! available! drugs,! but! in! terms! of!
duration! RNAi! sequences! were! more! effective! both! in! time! and! magnitude! in!
keeping!IOP!low.!When!dorzolamide!(Trusopt)!has!access!to!the!ciliary!processes!it!
can! effectively! inhibit! carbonic! anhydrases,! but! to! keep! a! sustained! effect! it! relies!
on! the! continuous! application! of! this! compound! (12).! On! the! contrary! the! topical!
application! of! siRNA! against! beta2! adrenergic! receptors! enabled! us! to! obtain! a!
significant! reduction! in! IOP! with! a! longYterm! effect.! This! may! be! one! of! the! most!
interesting!features!of!this!new!approach!for!the!treatment!of!ocular!hypertension!
and! glaucoma.! Moreover,! RNAi! sequence! has! been! designed! to! specifically! silence!
particular! subtype! of! adrenergic! receptor! with! successful! results.! These! results!
confirm!that!the!eye!as!an!ideal!target!for!a!RNAi!therapeutic!approach,!since!they!
also!imply!that!it!will!be!possible!to!diminish!the!final!RNAi!sequence!dose.!This!is!
a! relevant! point! in! order! to! minimize! sideYeffects,! both! offYtarget! effects,! those!
nonYspecific! RNAiYinduced! gene! silencing! ones! due! to! crossYreactions! with! other!
targets! of! limited! sequence! similarity! (13),! and! the! activation! of! the! interferon!
system! (14).! In! this! report! we! do! not! describe! the! analysis! of! either! offYtarget!
effects! or! inflammatory! response,! on! which! we! will! probably! provide! interesting!
information! in! the! near! future.! However,! if! we! examine! the! corneal! epithelium! or!
the! ocular! structures,! RNAi! sequence! treated! animals! have! not! shown! any!
structural! issue,! to! suggest! that! this! technology! could! be! an! interesting! new!
approach!for!the!treatment!of!glaucoma.!

In!a!remarkably!short!time!since!RNAi!natural!phenomenon!was!discovered!
in! model! organisms! (15),! this! technology! has! emerged! as! a! powerful! tool! for! the!
study!the!function!of!the!gene.!However,!in!the!last!few!years!the!therapeutic!use!of!
RNAi!is!taking!a!rising!path!with!interesting!results,!the!most!promising!being!the!
phase!I!clinical!trials!in!patients!with!neovascular!AMD.!Our!results!support!a!new!
generation! of! drugs! for! open! angle! glaucoma! treatment! and! also! provide! insights!
into!the!treatment!of!other!ocular!diseases.!

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