title: Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection.
abstract: RNA interference (RNAi)-based therapeutics have the potential to treat chronic hepatitis B virus (HBV) infection in a fundamentally different manner than current therapies. Using RNAi, it is possible to knock down expression of viral RNAs including the pregenomic RNA from which the replicative intermediates are derived, thus reducing viral load, and the viral proteins that result in disease and impact the immune system's ability to eliminate the virus. We previously described the use of polymer-based Dynamic PolyConjugate (DPC) for the targeted delivery of siRNAs to hepatocytes. Here, we first show in proof-of-concept studies that simple coinjection of a hepatocyte-targeted, N-acetylgalactosamine-conjugated melittin-like peptide (NAG-MLP) with a liver-tropic cholesterol-conjugated siRNA (chol-siRNA) targeting coagulation factor VII (F7) results in efficient F7 knockdown in mice and nonhuman primates without changes in clinical chemistry or induction of cytokines. Using transient and transgenic mouse models of HBV infection, we show that a single coinjection of NAG-MLP with potent chol-siRNAs targeting conserved HBV sequences resulted in multilog repression of viral RNA, proteins, and viral DNA with long duration of effect. These results suggest that coinjection of NAG-MLP and chol-siHBVs holds great promise as a new therapeutic for patients chronically infected with HBV.
authors: Arrowhead Research Corporation, Arrowhead Madison, Madison, Wisconsin 53711, USA. chris.wooddell@arrowres.com
authors: Christine I
authors: CI
authors: Wooddell
authors: David B
authors: DB
authors: Rozema
authors: Markus
authors: M
authors: Hossbach
authors: Matthias
authors: M
authors: John
authors: Holly L
authors: HL
authors: Hamilton
authors: Qili
authors: Q
authors: Chu
authors: Julia O
authors: JO
authors: Hegge
authors: Jason J
authors: JJ
authors: Klein
authors: Darren H
authors: DH
authors: Wakefield
authors: Claudia E
authors: CE
authors: Oropeza
authors: Jochen
authors: J
authors: Deckert
authors: Ingo
authors: I
authors: Roehl
authors: Kerstin
authors: K
authors: Jahn-Hofmann
authors: Philipp
authors: P
authors: Hadwiger
authors: Hans-Peter
authors: HP
authors: Vornlocher
authors: Alan
authors: A
authors: McLachlan
authors: David L
authors: DL
authors: Lewis
mesh_terms: D000116:Acetylgalactosamine / Q000031:analogs & derivatives / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002784:Cholesterol / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy; D005838:Genotype; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000235:genetics* / Q000628:therapy; D022781:Hepatocytes / Q000378:metabolism* / Q000821:virology; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000235:genetics; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics
chemical_list: D010455:Peptides; D034741:RNA, Small Interfering; D012367:RNA, Viral; D002784:Cholesterol; D000116:Acetylgalactosamine