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

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Abstract

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.

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Acknowledgements

Pedro Renato de Paula Brandão, Simoneide S. Titze-de-Almeida, and Ricardo Titze-de-Almeida are members of the Network for Translational Neuroscience-International Consortium for Academic Cooperation in Experimental and Clinical Studies Regarding Neurodegenerative Diseases (http://dgp.cnpq.br/dgp/espelhogrupo/5933421119277338).

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Authors and Affiliations

  1. Technology for Gene Therapy Laboratory, Central Institute of Sciences, University of Brasília/FAV, Brasília, DF, Brazil

    Pedro Renato de Paula Brandão, Simoneide S. Titze-de-Almeida & Ricardo Titze-de-Almeida

  2. Neuroscience and Behavior Lab, Biological Sciences Institute, University of Brasília, Brasília, DF, Brazil

    Pedro Renato de Paula Brandão

  3. Brasília University Hospital, University of Brasília, Brasília, DF, Brazil

    Pedro Renato de Paula Brandão

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  1. Pedro Renato de Paula Brandão
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Correspondence to Ricardo Titze-de-Almeida.

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Pedro Renato de Paula Brandão, Simoneide S. Titze-de-Almeida, and Ricardo Titze-de-Almeida have no conflicts of interest that are directly relevant to the content of this study.

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de Paula Brandão, P.R., Titze-de-Almeida, S.S. & Titze-de-Almeida, R. Leading RNA Interference Therapeutics Part 2: Silencing Delta-Aminolevulinic Acid Synthase 1, with a Focus on Givosiran. Mol Diagn Ther 24, 61–68 (2020). https://doi.org/10.1007/s40291-019-00438-6

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