Delving into the Latest Updates on CIDEB RNAi program with Synapse

Overview

Basic Info

Drug Type

siRNA

Synonyms

CIDEB RNAi program (Regeneron Pharmaceuticals), CIDEB(Regeneron)

Target

CIDEB

Mechanism

CIDEB inhibitors(cell death inducing DFFA like effector b inhibitors)

Therapeutic Areas

Digestive System Disorders

Active Indication

Nonalcoholic Steatohepatitis

Inactive Indication-

Originator Organization

Regeneron Pharmaceuticals, Inc.

Active Organization

Alnylam Pharmaceuticals, Inc.

Regeneron Pharmaceuticals, Inc.

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Abnormal lipid metabolism is one of many factors that contribute to the development of ulcerative colitis (UC). As a lipid droplet-associated protein, Cideb facilitated the export of lipids from enterocytes and promoted intestinal lipid absorption. We found that Cideb was upregulated in the colonic mucosa of both UC patients and dextran sodium sulfate (DSS)-induced mouse colitis, but its roles in the pathogenesis of UC are still ill-defined.

METHODS:

Acute colitis was induced with DSS in Cideb-null and wild-type mice, and the inflammation and oxidative stress were evaluated in the colonic mucosa. Moreover, triglyceride accumulation and oxidative stress were further analyzed in polarized Caco-2 cells with overexpression of Cideb.

RESULTS:

Our present data indicated that Cideb-null mice were more susceptible to DSS-induced colitis, and consumption of a high-fat diet exacerbated the deterioration of DSS-induced colitis in Cideb-null mice. Moreover, Cideb deficiency increased the colonic oxidative stress in DSS-treated mice and more significant under a high-fat diet condition. In exploring the mechanism, we found that Cideb deficiency elevated the lipid content in both feces and the colonic mucosa of DSS-treated mice, especially those fed with a high-fat diet. The in vitro evidence proved that Cideb expression reduced triglyceride accumulation and oxidative stress in polarized Caco-2 cells in the presence of oleic acid.

CONCLUSIONS:

Our data suggest that Cideb plays a protective role against the development of UC by reducing the lipid accumulation and oxidative damage in the colonic mucosa. Therefore, Cideb could be a potential therapeutic target for UC.

01 Feb 2012·Diabetes/metabolism research and reviewsQ3 · MEDICINE

Cell death‐inducing DFF45‐like effector b (Cideb) is present in pancreatic beta‐cells and involved in palmitate induced beta‐cell apoptosis

Q3 · MEDICINE

Article

Author: Li, F. F. ; Gu, Y. ; Song, Y. ; Zhang, L. J. ; Liu, F. ; Xue, L. ; Zhang, J. ; Dong, W. P. ; Jiang, L. N. ; Li, Q. ; Li, H. ; Wang, J. ; Zhang, L. Y. ; Ye, J.

Abstract:

Background:

Excessive accumulation of long‐chain fatty acids in the pancreatic islets is associated with beta cell dysfunction and ultimately contributes to the pathogenesis of type 2 diabetes. It has been well proved that the cell death‐inducing DFF45‐like effector b (Cideb) is involved in cell apoptosis and lipid metabolism. However, the expression and function of Cideb in endocrine pancreas remain to be investigated.

Methods:

By using reverse transcript polymerase chain reaction, immunohistochemistry and Western blot, we observed the expression of Cideb in pancreas tissues and clonal beta‐cell lines. The physiological role of Cideb was examined under the free fatty acid (FFA) administration and Cideb ribonucleic acid interference, and further analysis on apoptosis was measured by terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick end labelling assay and caspase‐3 activity. Nile red staining and quantitative evaluation of triglyceride were used to detect the lipid accumulation. The changes in esterification of FFA were traced by radiolabelled palmitate.

Results:

Cideb was abundantly expressed in pancreas and mainly localized in beta cells. FFAs, especially palmitate, induced an obvious increase of Cideb expression in beta cell lines. Adenoviral‐mediated overexpression of Cideb increased the apoptosis, whereas ribonucleic acid interference‐based Cideb depletion in beta‐TC3 cells had no effect on apoptosis in normal condition. Palmitate supplementation led to beta cell lipoapoptosis, and Cideb silencing exacerbated the apoptosis induced by palmitate, reduced intracellular triglyceride content and aggravated FFA overload in beta cells.

Conclusions:

The present results suggest that increased Cideb expression upon palmitate exposure may be involved in beta cell lipoapoptosis through its influence on conversion of FFAs to lipid esters in lipid droplets. Copyright © 2011 John Wiley & Sons, Ltd.

01 May 1998·The EMBO journalQ1 · BIOLOGY

CIDE, a novel family of cell death activators with homology to the 45kDa subunit of the DNA fragmentation factor

Q1 · BIOLOGY

Article

Author: Xiaoyu Wu ; Takeyoshi Koseki ; Gabriel Núñez ; Shu Chen ; Naohiro Inohara

DFF45 is a subunit of the DNA fragmentation factor (DFF) that is cleaved by caspase-3 during apoptosis. However, the mechanism by which DFF45 regulates apoptotic cell death remains poorly understood. Here we report the identification and characterization of two mammalian genes, CIDE-A and CIDE-B, encoding highly related proteins with homology to the N-terminal region of DFF45. CIDE-A and CIDE-B were found to activate apoptosis in mammalian cells, which was inhibited by DFF45 but not by caspase inhibitors. Expression of CIDE-A induced DNA fragmentation in 293T cells, which was inhibited by DFF45, further suggesting that DFF45 inhibits the apoptotic activities of CIDEs. In addition to mammalian CIDE-A and CIDE-B, we identified DREP-1, a Drosophila melanogaster homolog of DFF45 that could inhibit CIDE-A-mediated apoptosis. Mutant analysis revealed that the C-terminal region of CIDE-A was necessary and sufficient for killing whereas the region with homology to DFF45 located in the N-terminus was required for DFF45 to inhibit CIDE-A-induced apoptosis. CD95/Fas-mediated apoptosis was enhanced by CIDEs but inhibited by DFF45. These studies suggest that DFF45 is evolutionarily conserved and implicate CIDEs as DFF45-inhibitable effectors that promote cell death and DNA fragmentation.

100 Deals associated with CIDEB RNAi program

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Preclinical	US	Alnylam Pharmaceuticals, Inc.	27 Jul 2022
Nonalcoholic Steatohepatitis	Preclinical	US	Regeneron Pharmaceuticals, Inc.	27 Jul 2022