| 2. |
- Coelho, Teresa, et al.
(författare)
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Safety and efficacy of RNAi therapy for transthyretin amyloidosis
- 2013
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Ingår i: The New England journal of medicine. - 1533-4406. ; 369:9, s. 819-29
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Tidskriftsartikel (refereegranskat)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.).
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| 3. |
- Friedman, Rachel S., et al.
(författare)
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Beyond the community in participatory forest management : A governance network perspective
- 2020
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Ingår i: Land use policy. - : Elsevier BV. - 0264-8377 .- 1873-5754. ; 97
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Tidskriftsartikel (refereegranskat)abstract
- Governance of the environment and natural resources involves interests of multiple stakeholders at different scales. In community-based forest management, organisations outside of communities play important roles in achieving multiple social and ecological objectives. How and when these organisations play a role in the community-based forest management process remains a key question. We applied social network analysis to a case study in Indonesian Borneo to better understand the evolution of interactions between organisational actors, and with communities. NGOs featured most prominently in initiating the permit process, implementing management, and providing other support activities, while also being well-connected to donors and government actors. The network configurations indicated significant cooperation among organisations when initiating the community forest process, while bridging between village and organisational levels characterised all stages of the community forest process. While community-based forest management often evokes images of grassroots efforts and broad local capacity to manage forests, reality shows a more dynamic and heterogeneous picture and broader involvement of different actor types and motivations in Indonesia. These findings can be applied to other countries implementing and expanding their decentralised forest policies.
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