Leading RNA Interference Therapeutics Part 2: Silencing Delta-Aminolevulinic Acid Synthase 1, with a Focus on Givosiran

Citations of this article
Mendeley users who have this article in their library.

You may have access to this PDF.


In November 2019 givosiran became the second small interfering RNA (siRNA)-based drug to receive US Food and Drug Administration (FDA) approval, it has been developed for the treatment of acute intermittent porphyria (AIP), a disorder characterized by life-threatening acute neurovisceral attacks. The porphyrias are a group of disorders in which enzymatic deficiencies in heme production lead to toxic accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), which are involved in the neurovisceral attacks. Givosiran acts as a conventional siRNA to trigger RNA interference (RNAi)-mediated gene silencing on delta-ALA synthase 1 (ALAS1), thus returning ALA and PBG metabolites to the physiological level to attenuate further neurotoxicity. Givosiran makes use of a new hepatic-delivery system that conjugates three GalNac (N-acetylgalactosamine) molecules to the siRNA passenger strand. GalNac binds to the liver asialoglycoprotein receptor, favoring the internalization of these GalNac-conjugated siRNAs into the hepatic cells. In a phase I study, subcutaneous monthly administration of givosiran 2.5 mg/kg reduced > 90% of ALA and PBG content. This siRNA is being analyzed in ENVISION (NCT03338816), a phase III, multicenter, placebo-controlled randomized controlled trial. In preliminary results, givosiran achieved clinical endpoints for AIP, reducing urinary ALA levels, and presented a safety profile that enabled further drug development. The clinical performance of givosiran revealed that suppression of ALAS1 by GalNac-decorated siRNAs represents an additional approach for the treatment of patients with AIP that manifests recurrent acute neurovisceral attacks.




de Paula Brandão, P. R., Titze-de-Almeida, S. S., & Titze-de-Almeida, R. (2020, February 1). Leading RNA Interference Therapeutics Part 2: Silencing Delta-Aminolevulinic Acid Synthase 1, with a Focus on Givosiran. Molecular Diagnosis and Therapy. Adis. https://doi.org/10.1007/s40291-019-00438-6

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free