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

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. Th...

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Bibliographic Details
Published in:Molecular diagnosis & therapy 2020-02, Vol.24 (1), p.61-68
Main Authors: de Paula Brandão, Pedro Renato, Titze-de-Almeida, Simoneide S., Titze-de-Almeida, Ricardo
Format: Article
Language:English
Subjects:
Abdomen
Aminolevulinic acid
Biomedical and Life Sciences
Biomedicine
Biosynthesis
Bone marrow
Cancer Research
Cytochrome
Drug development
Enzymes
Gene expression
Gene silencing
Guillain-Barre syndrome
Heme
Hemoglobin
Human Genetics
Interference
Internalization
Laboratory Medicine
Lead content
Liver
Metabolism
Metabolites
Molecular Medicine
Neurotoxicity
Patients
Pharmacotherapy
Physiology
Porphyria
Regulatory agencies
Review Article
Ribonucleic acid
RNA
RNA-mediated interference
siRNA
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Summary: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.
ISSN:1177-1062
1179-2000
DOI:10.1007/s40291-019-00438-6