title: Novel hydrophobically modified asymmetric RNAi compounds (sd-rxRNA) demonstrate robust efficacy in the eye.
abstract: OBJECTIVE
  The major challenges of developing an RNAi therapeutic include efficient delivery to and entry into the cell type of interest. Conventional ("naked" and chemically stabilized) small interfering RNAs (siRNAs) have been used in the eye in the past but they demonstrated limited clinical efficacy. Here we investigated a recently developed class of small, hydrophobic, asymmetric RNAi compounds. These compounds, termed "self-delivering rxRNAs" (sd-rxRNA(®)), are extensively modified, have a small duplex region of <15 base pairs, contain a fully phosphorothioated single-stranded tail, and readily enter cells and tissues without the requirement for a delivery vehicle.
  
  
  METHODS
  We compared sd-rxRNA compounds with stabilized siRNAs in vitro (in ARPE-19 cells) and in vivo (intravitreal injection in mouse and rabbit eyes). Specifically, we investigated the retinal uptake, distribution, efficacy, and preliminary safety of sd-rxRNAs.
  
  
  RESULTS
  Treatment with sd-rxRNAs resulted in uniform cellular uptake and full retina penetration in both animal models while no detectable cellular uptake was observed with stabilized siRNAs either in vitro or in vivo. Further, both in vitro and in vivo delivery (without any transfection reagent or formulation) resulted in a significant reduction of the targeted mRNA levels, which lasted 14-21 days in vivo. Retinal morphology and function were unaltered following a single administration of sd-rxRNAs.
  
  
  CONCLUSIONS
  These data support the potential of developing sd-rxRNAs as a therapeutic for ocular disease.
authors.affiliation: 1 RXi Pharmaceuticals, Corp. , Westborough, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Byrne
authors.forename: Radouil
authors.initials: R
authors.lastname: Tzekov
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Amanda
authors.initials: A
authors.lastname: Rodgers
authors.forename: James
authors.initials: J
authors.lastname: Cardia
authors.forename: Glenna
authors.initials: G
authors.lastname: Ford
authors.forename: Katherine
authors.initials: K
authors.lastname: Holton
authors.forename: Lakshmipathi
authors.initials: L
authors.lastname: Pandarinathan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lapierre
authors.forename: William
authors.initials: W
authors.lastname: Stanney
authors.forename: Karen
authors.initials: K
authors.lastname: Bulock
authors.forename: Sharon
authors.initials: S
authors.lastname: Shaw
authors.forename: Lyn
authors.initials: L
authors.lastname: Libertine
authors.forename: Kevin
authors.initials: K
authors.lastname: Fettes
authors.forename: Anastasia
authors.initials: A
authors.lastname: Khvorova
authors.forename: Shalesh
authors.initials: S
authors.lastname: Kaushal
authors.forename: Pamela
authors.initials: P
authors.lastname: Pavco
mesh_terms: D000818:Animals; D002460:Cell Line; D005128:Eye Diseases / Q000628:therapy; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D058449:Intravitreal Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D011817:Rabbits; D012160:Retina / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering