New compound treats both blindness and diabetes in animal studies

July 10, 2014

In a new study led by UC San Francisco (UCSF) scientists, a chemical compound designed to precisely target part of a crucial cellular quality-control network provided significant protection, in rats and mice, against degenerative forms of blindness and diabetes.

In addition to opening a promising drug-development path for the wide range of diseases caused by cell loss, the new research offers a new view of the workings of the unfolded protein response (UPR), a cellular "life-or-death" signaling network: When cells are under stress, the UPR works to ensure that they produce properly configured proteins, but those cells not up to this task are quickly prompted by the UPR to self-destruct.

A component of the UPR known as the IRE1 pathway has generally been thought to handle the protective aspects of this response, promoting cell survival by providing cells with the biological resources they need to cope with stress, while a complementary pathway, called PERK, has been associated with .

But in the new research, published in the July 10, 2014 edition of Cell, when researchers used KIRA6, a small-molecule kinase inhibitor they designed to inhibit the actions of IRE1 alpha —the molecular sensor that triggers the IRE1 pathway—they blocked cell death and preserved function in experimental models of two human diseases.

In two rat models of retinitis pigmentosa, a disease in which light-sensing cells in the eye progressively die off, causing blindness, KIRA6 preserved both the number of these cells and visual function. And in mice from a strain known as Akita, which carry a genetic mutation that causes diabetes in early life as stressed insulin-producing beta cells of the pancreas degenerate, KIRA6 protected beta cells from cell death, leading to a two-fold increase in insulin production and improving blood glucose control.

"This is a huge advance in our field," said co-senior author Scott A. Oakes, MD, associate professor of pathology at UCSF. "On the surface these would seem to be two very different diseases, but IRE1-induced cell death is at the root of both of them."

The results are the culmination of "a gigantic project," first to establish that the IRE1 pathway could drive degenerative disease, and then to design and test compounds to head off the damage, said UCSF's Feroz Papa, MD, PhD, associate professor of medicine and co-senior author, and a member of the California Institute for Quantitative Biosciences. "It took four years, over a hundred separate experiments in various contexts—not counting replications—and involved 24 researchers working in seven labs labs across four cities."

KIRA6 is the latest in a series of compounds (the acronym stands for "Kinase-Inhibiting RNase Attenuators) that were originally designed and synthesized in the labs of study co-authors Dustin J. Maly, PhD, associate professor of chemistry at The University of Washington, Seattle, and Bradley J. Backes, PhD, associate professor of medicine at UCSF.

"While KIRA6 showed efficacy in animals," said Papa, "it is important to stress that more optimization through medicinal chemistry efforts is needed to develop this class of compounds to the stage where they could be tested for efficacy in humans through clinical trials."

Oakes and Papa said that support from the Cleveland, Ohio-based Harrington Discovery Institute was crucial to sustaining this complex collaboration. Both scientists were 2013 winners of Scholar-Innovator Awards from the Institute, which is part of The Harrington Project for Development and Discovery a $250 million national model to accelerate the development of medical breakthroughs by physician-scientists into medicines that benefit patients. Other critical support for the work came from the National Institutes of Health, the Juvenile Diabetes Research Foundation, the Burroughs Wellcome Fund, the American Cancer Society, and the Howard Hughes Medical Institute.

Explore further: Chinese herbal extract may help kill off pancreatic cancer cells

Related Stories

Chinese herbal extract may help kill off pancreatic cancer cells

July 1, 2014
A diagnosis of pancreatic cancer—the fourth most common cause of cancer death in the U.S.—can be devastating. Due in part to aggressive cell replication and tumor growth, pancreatic cancer progresses quickly and has a ...

A molecule central to diabetes is uncovered

August 8, 2012
(Medical Xpress) -- At its most fundamental level, diabetes is a disease characterized by stress — microscopic stress that causes inflammation and the loss of insulin production in the pancreas, and system-wide stress ...

Cell stress inflames the gut: New insights into chronic bowel inflammation

June 23, 2014
Inflammatory bowel disease (IBD) is a common condition in western industrialized countries. What triggers it, however, is not yet fully understood. Nutrition researchers at Technische Universität München (TUM) have now ...

Pathway identified in human lymphoma points way to new blood cancer treatments

November 21, 2012
A pathway called the "Unfolded Protein Response," or UPR, a cell's way of responding to unfolded and misfolded proteins, helps tumor cells escape programmed cell death during the development of lymphoma.

Specific protein may help beta cells survive in type 1 diabetes

June 9, 2014
Researchers find therapeutic potential of MANF protein to reduce beta cell stress in type 1 diabetes.

Sleep-deprived mice show connections among lack of shut-eye, diabetes, age

December 11, 2013
Sleep, or the lack of it, seems to affect just about every aspect of human physiology. Yet, the molecular pathways through which sleep deprivation wreaks its detrimental effects on the body remain poorly understood. Although ...

Recommended for you

Link between cells associated with aging and bone loss

August 21, 2017
Mayo Clinic researchers have reported a causal link between senescent cells - the cells associated with aging and age-related disease - and bone loss in mice. Targeting these cells led to an increase in bone mass and strength. ...

Gut microbes may talk to the brain through cortisol

August 21, 2017
Gut microbes have been in the news a lot lately. Recent studies show they can influence human health, behavior, and certain neurological disorders, such as autism. But just how do they communicate with the brain? Results ...

Are stem cells the link between bacteria and cancer?

August 17, 2017
Gastric carcinoma is one of the most common causes of cancer-related deaths, primarily because most patients present at an advanced stage of the disease. The main cause of this cancer is the bacterium Helicobacter pylori, ...

Two-step process leads to cell immortalization and cancer

August 17, 2017
A mutation that helps make cells immortal is critical to the development of a tumor, but new research at the University of California, Berkeley suggests that becoming immortal is a more complicated process than originally ...

New Pathology Atlas maps genes in cancer to accelerate progress in personalized medicine

August 17, 2017
A new Pathology Atlas is launched today with an analysis of all human genes in all major cancers showing the consequence of their corresponding protein levels for overall patient survival. The difference in expression patterns ...

Female mouse embryos actively remove male reproductive systems

August 17, 2017
A protein called COUP-TFII determines whether a mouse embryo develops a male reproductive tract, according to researchers at the National Institutes of Health and their colleagues at Baylor College of Medicine, Houston. The ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.