title: Safety and efficacy of RNAi therapy for transthyretin amyloidosis.
abstract: BACKGROUND
  Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin.
  
  
  METHODS
  We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers.
  
  
  RESULTS
  Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively.
  
  
  CONCLUSIONS
  ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).
authors.affiliation: Unidade Clinica de Paramiloidose, Hospital de Santo Antonio, Porto, Portugal. tcoelho@netcabo.pt
authors.forename: Teresa
authors.initials: T
authors.lastname: Coelho
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.forename: Ana
authors.initials: A
authors.lastname: Silva
authors.forename: Pierre
authors.initials: P
authors.lastname: Lozeron
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: Timothy
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authors.lastname: Mant
authors.forename: Javier
authors.initials: J
authors.lastname: Perez
authors.forename: Joseph
authors.initials: J
authors.lastname: Chiesa
authors.forename: Steve
authors.initials: S
authors.lastname: Warrington
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tranter
authors.forename: Malathy
authors.initials: M
authors.lastname: Munisamy
authors.forename: Rick
authors.initials: R
authors.lastname: Falzone
authors.forename: Jamie
authors.initials: J
authors.lastname: Harrop
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cehelsky
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bettencourt
authors.forename: Mary
authors.initials: M
authors.lastname: Geissler
authors.forename: James S
authors.initials: JS
authors.lastname: Butler
authors.forename: Alfica
authors.initials: A
authors.lastname: Sehgal
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Meyers
authors.forename: Qingmin
authors.initials: Q
authors.lastname: Chen
authors.forename: Todd
authors.initials: T
authors.lastname: Borland
authors.forename: Renta M
authors.initials: RM
authors.lastname: Hutabarat
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Clausen
authors.forename: Rene
authors.initials: R
authors.lastname: Alvarez
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Christina
authors.initials: C
authors.lastname: Gamba-Vitalo
authors.forename: Saraswathy V
authors.initials: SV
authors.lastname: Nochur
authors.forename: Akshay K
authors.initials: AK
authors.lastname: Vaishnaw
authors.forename: Dinah W Y
authors.initials: DW
authors.lastname: Sah
authors.forename: Jared A
authors.initials: JA
authors.lastname: Gollob
authors.forename: Ole B
authors.initials: OB
authors.lastname: Suhr
mesh_terms: D000293:Adolescent; D000328:Adult; D028227:Amyloid Neuropathies, Familial / Q000235:genetics / Q000628:therapy*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008081:Liposomes; D008252:Macaca fascicularis; D008297:Male; D053769:Nanocapsules; D011228:Prealbumin / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D008081:Liposomes; D053769:Nanocapsules; D011228:Prealbumin; D034741:RNA, Small Interfering