(HealthDay News) – Two formulations of anti-transthyretin small interfering RNA suppress production of transthyretin, providing a potential treatment for transthyretin amyloidosis, according to a study published in the Aug. 29 issue of the New England Journal of Medicine.

Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. Teresa Coelho, MD, from the Hospital de Santo Antonio in Porto, Portugal, and colleagues tested two formulations of anti-transthyretin small interfering RNA, encapsulated in lipid nanoparticles, in single-dose, placebo-controlled phase 1 trials to assess their effect on transthyretin levels. ALN-TTR01 (dose 0.01–1mg/kg) was tested in 32 patients with transthyretin amyloidosis, while ALN-TTR02 (dose 0.01–0.5mg/kg) was tested in 17 healthy volunteers.

In the two trials, the researchers identified rapid, dose-dependent, and durable reduction of transthyretin levels. ALN-TTR01 suppressed transthyretin at a dose of 1mg/kg, with a mean reduction of 38% vs. placebo at day seven. Similar reductions were seen in levels of mutant and non-mutant forms of transthyretin. The mean reductions in transthyretin levels ranged from 82.3–86.8% at doses of 0.15–0.3mg/kg for ALN-TTR02, with reductions of 56.6–67.1% seen at 28 days. The reductions were mediated by RNA interference. In 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively, there were mild-to-moderate infusion-related reactions.

“ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and non-mutant forms of transthyretin, establishing proof of concept for RNA interference therapy targeting messenger RNA transcribed from a disease-causing gene,” the authors write.

The study was funded by Alnylam Pharmaceuticals.

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