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Safety and efficacy...
Safety and efficacy of RNAi therapy for transthyretin amyloidosis
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Coelho, Teresa (författare)
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Adams, David (författare)
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Silva, Ana (författare)
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visa fler...
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Lozeron, Pierre (författare)
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Hawkins, Philip N (författare)
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Mant, Timothy (författare)
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Perez, Javier (författare)
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Chiesa, Joseph (författare)
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Warrington, Steve (författare)
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Tranter, Elizabeth (författare)
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Munisamy, Malathy (författare)
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Falzone, Rick (författare)
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Harrop, Jamie (författare)
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Cehelsky, Jeffrey (författare)
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Bettencourt, Brian R (författare)
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Geissler, Mary (författare)
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Butler, James S (författare)
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Sehgal, Alfica (författare)
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Meyers, Rachel E (författare)
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Chen, Qingmin (författare)
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Borland, Todd (författare)
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Hutabarat, Renta M (författare)
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Clausen, Valerie A (författare)
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Alvarez, Rene (författare)
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Fitzgerald, Kevin (författare)
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Gamba-Vitalo, Christina (författare)
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Nochur, Saraswathy V (författare)
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Vaishnaw, Akshay K (författare)
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Sah, Dinah W Y (författare)
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Gollob, Jared A (författare)
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- Suhr, Ole B (författare)
- Umeå universitet,Medicin
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(creator_code:org_t)
- 2013
- 2013
- Engelska.
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Ingår i: The New England journal of medicine. - 1533-4406. ; 369:9, s. 819-29
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.).
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Coelho, Teresa
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Adams, David
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Silva, Ana
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Lozeron, Pierre
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Hawkins, Philip ...
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Mant, Timothy
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visa fler...
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Perez, Javier
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Chiesa, Joseph
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Warrington, Stev ...
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Tranter, Elizabe ...
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Munisamy, Malath ...
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Falzone, Rick
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Harrop, Jamie
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Cehelsky, Jeffre ...
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Bettencourt, Bri ...
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Geissler, Mary
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Butler, James S
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Sehgal, Alfica
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Meyers, Rachel E
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Chen, Qingmin
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Borland, Todd
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Hutabarat, Renta ...
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Clausen, Valerie ...
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Alvarez, Rene
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Fitzgerald, Kevi ...
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Gamba-Vitalo, Ch ...
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Nochur, Saraswat ...
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Vaishnaw, Akshay ...
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Sah, Dinah W Y
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Gollob, Jared A
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Suhr, Ole B
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visa färre...
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The New England ...
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Umeå universitet