RNAi therapeutic

An RNAi therapeutic is a drug whose mechanism of action is based on RNA interference (RNAi).

properties

RNAi therapeutics are ribonucleic acids or analogs (mostly shRNA ) that bind sequence-specifically to the mRNA of a certain gene . After the binding, the RNA interference takes place, which consists of a breakdown of the RNA by the nuclease Dicer into short fragments, which then serve as a template for generating siRNA . The binding of the shRNA to the mRNA causes the mRNA to be broken down and the translation of the mRNA of the gene is interrupted, so that the protein of the gene is no longer produced in the affected cell . The additional use of the fragments to generate siRNA makes the process self-reinforcing as long as the fragment of this mRNA is formed and can be used as a template.

During RNAi, the function of a gene is temporarily inactivated ( gene knockdown ). Due to the sequence specificity, an RNAi therapeutic can in principle be used against any mRNA and thus against any disease that can be treated by gene knockdown. One problem with the method is the comparatively rapid breakdown of RNA in the bloodstream (short biological half-life ) and the targeted absorption of the RNAi therapeutic agent, if possible, only in diseased cells or tissues of an organism.

use

Various RNAi therapeutics are in clinical trials in 2017, including:

TKM-Ebola (against the Ebola virus ),
Patisiran (used to treat hereditary ATTR amyloidosis , hATTR),
QPI-1002 (for the treatment of acute kidney damage ) and
QPI-1007 (for the treatment of non-arteritic anterior ischemic optic neuropathy ).
Inclisiran / ALN-PCSsc (used to treat familial hypercholesterolemia )
Fitusiran (used to treat haemophilia )
Givosiran / ALN-AS1 (for the treatment of acute intermittent porphyria )

The clinical approval process for bevasiranib (for the treatment of macular degeneration ) has been discontinued.

Individual evidence

^ Y. Zhou, C. Zhang, W. Liang: Development of RNAi technology for targeted therapy - a track of siRNA based agents to RNAi therapeutics. In: Journal of controlled release: official journal of the Controlled Release Society. Volume 193, November 2014, pp. 270-281, doi : 10.1016 / j.jconrel.2014.04.044 , PMID 24816071 .
^ R. Titze-de-Almeida, C. David, SS Titze-de-Almeida: The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market. In: Pharmaceutical research. Volume 34, Number 7, July 2017, pp. 1339-1363, doi : 10.1007 / s11095-017-2134-2 , PMID 28389707 .
↑ ML Bobbin, JJ Rossi: RNA Interference (RNAi) -Based Therapeutics: Delivering on the Promise? In: Annual review of pharmacology and toxicology. Volume 56, 2016, pp. 103-122, doi : 10.1146 / annurev-pharmtox-010715-103633 , PMID 26738473 .
↑ The Medicines Company and Alnylam Pharmaceuticals Announce Agreement with FDA on Phase III Clinical Program for Inclisiran ( Memento of 26 June 2017 Internet Archive ), PM Alnylam of 26 April 2017 called on July 24, 2017
↑ Alnylam and Sanofi Genzyme Report Positive Results from Ongoing Phase 2 Open-Label Extension Study with Investigational RNAi Therapeutic Fitusiran in Patients with Hemophilia A and B With or Without Inhibitors ( Memento from July 18, 2017 in the Internet Archive ), PM Alnylam from 10. July 2017. Retrieved July 24, 2017
↑ Alnylam and Sanofi Genzyme Initiate ATLAS Phase 3 Program with Investigational RNAi Therapeutic Fitusiran in Patients with Hemophilia A and B with or without Inhibitors ( Memento of July 10, 2017 in the Internet Archive ), PM Alnylam of July 7, 2017, accessed on May 24, 2017. July 2017
↑ Initial Evidence of Clinical Activity Shown with Givosiran (ALN-AS1) in Acute Intermittent Porphyria Patients with Recurrent Attacks ( Memento from February 7, 2017 in the Internet Archive ), PM Alnylam from March 12, 2016, accessed on July 24, 2017 2017
↑ H. Ledford: Drug giants turn their backs on RNA interference. In: Nature. Volume 468, Number 7323, November 2010, p. 487, doi : 10.1038 / 468487a , PMID 21107398 .

[1] Y. Zhou, C. Zhang, W. Liang: Development of RNAi technology for targeted therapy - a track of siRNA based agents to RNAi therapeutics. In: Journal of controlled release: official journal of the Controlled Release Society. Volume 193, November 2014, pp. 270-281, doi : 10.1016 / j.jconrel.2014.04.044 , PMID 24816071 .

[2] R. Titze-de-Almeida, C. David, SS Titze-de-Almeida: The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market. In: Pharmaceutical research. Volume 34, Number 7, July 2017, pp. 1339-1363, doi : 10.1007 / s11095-017-2134-2 , PMID 28389707 .

[3] ML Bobbin, JJ Rossi: RNA Interference (RNAi) -Based Therapeutics: Delivering on the Promise? In: Annual review of pharmacology and toxicology. Volume 56, 2016, pp. 103-122, doi : 10.1146 / annurev-pharmtox-010715-103633 , PMID 26738473 .

[4] The Medicines Company and Alnylam Pharmaceuticals Announce Agreement with FDA on Phase III Clinical Program for Inclisiran ( Memento of 26 June 2017 Internet Archive ), PM Alnylam of 26 April 2017 called on July 24, 2017

[5] Alnylam and Sanofi Genzyme Report Positive Results from Ongoing Phase 2 Open-Label Extension Study with Investigational RNAi Therapeutic Fitusiran in Patients with Hemophilia A and B With or Without Inhibitors ( Memento from July 18, 2017 in the Internet Archive ), PM Alnylam from 10. July 2017. Retrieved July 24, 2017

[6] Alnylam and Sanofi Genzyme Initiate ATLAS Phase 3 Program with Investigational RNAi Therapeutic Fitusiran in Patients with Hemophilia A and B with or without Inhibitors ( Memento of July 10, 2017 in the Internet Archive ), PM Alnylam of July 7, 2017, accessed on May 24, 2017. July 2017

[7] Initial Evidence of Clinical Activity Shown with Givosiran (ALN-AS1) in Acute Intermittent Porphyria Patients with Recurrent Attacks ( Memento from February 7, 2017 in the Internet Archive ), PM Alnylam from March 12, 2016, accessed on July 24, 2017 2017

[8] H. Ledford: Drug giants turn their backs on RNA interference. In: Nature. Volume 468, Number 7323, November 2010, p. 487, doi : 10.1038 / 468487a , PMID 21107398 .