• Teresa Coelho, David Adams, Ana Silva, Pierre Lozeron, Philip N Hawkins, Timothy Mant, Javier Perez, Joseph Chiesa, Steve Warrington, Elizabeth Tranter, Malathy Munisamy, Rick Falzone, Jamie Harrop, Jeffrey Cehelsky, Brian R Bettencourt, Mary Geissler, James S Butler, Alfica Sehgal, Rachel E Meyers, Qingmin Chen, Todd Borland, Renta M Hutabarat, Valerie A Clausen, Rene Alvarez, Kevin Fitzgerald, Christina Gamba-Vitalo, Saraswathy V Nochur, Akshay K Vaishnaw, Dinah W Y Sah, Jared A Gollob, and Ole B Suhr.
• Unidade Clinica de Paramiloidose, Hospital de Santo Antonio, Porto, Portugal. tcoelho@netcabo.pt
• N. Engl. J. Med.. 2013 Aug 29;369(9):819-29.

BackgroundTransthyretin 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.MethodsWe 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.ResultsRapid, 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.ConclusionsALN-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.).

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