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Msg  34848 of 34916  at  7/8/2020 6:16:49 AM  by


The following message was updated on 7/8/2020 6:17:19 AM.

NAFLD article using siRNA

Barbier-Torres, L., Fortner, K.A., Iruzubieta, P. et al. Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation. Nat Commun 11, 3360 (2020).

from discussion portion of paper:
Currently, all the therapeutic drugs undergoing clinical trials for NASH are small molecules (what about ARO-HSD??). Our data show, in contrast, that the use of siRNA to reduce the levels of MCJ in the liver may constitute an alternative therapeutic strategy16,17. Following the initial excitement for the use of siRNA for therapeutic purposes, the actual development of successful siRNA therapies has been a long and complicated process. A critical challenge for the efficient development of siRNA-based therapies has been the design of delivery systems that specifically target the tissue of interest. In spite of this, delivery to the liver has produced major success and resulted in some FDA-approved drugs39. The most common delivery system for siRNA to the liver has long been LNP and the first LNP-formulated siRNA-based drug (Patisiran) was approved in 2018 for the treatment of hATTR (hereditary transthyretin-mediated) amyloidosis40. However, due to potential secondary effects during prolonged treatments, particularly on the immune system, GalNAc was developed as an alternative delivery system for the liver that specifically targets hepatocytes28,29. GalNAc-siRNA conjugates are synthesized by incorporating synthetic triantennary GalNAc to a chemically modified siRNA. GalNAc is specifically delivered to hepatocytes due to the presence of the hepatocyte-specific asialoglycoprotein receptor28,29,41,42. Unlike LNPs, GalNAc-siRNA conjugates can be delivered by subcutaneous administration (s.c.), which can potentially allow for self-administration. The first GalNAc-conjugated siRNA drug (Givosiran) was FDA approved in 2019 for the treatment of acute hepatic porphyria. There are over 30 clinical trials with different GalNAc-conjugated siRNA to treat multiple clinical indications43. Here we show that siMCJ formulated into LNP or GalNAc has efficacy in reducing liver steatosis and fibrosis in multiple NASH mouse models. To date no other siRNA-based drugs have been tested in human clinical trials, therefore GalNAc-siMCJ could be one of the first therapies tested in the future.

Overall, we show that liver-specific delivery systems for MCJ safely reduce steatosis, inflammation, and fibrosis using different mouse models of NAFLD. Thus, treatment with siMCJ could emerge as a potential alternative therapeutic approach for this disease.

M.R. has a patent application related to this work. M.L.M.-C. and J.A. have a patent application that could be related to this work. M.R. is a co-founder and a member of the Scientific Advisory Board of Mitotherapeutix LLC. M.L.M.-C. is a member of the Scientific Advisory Board of Mitotherapeutix LLC. K.A.F. has received funding through Mitorherapeutix. F. T. and D. O. are employees of Alnylam Pharmaceuticals with salary and stock options.

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