Featured Research

from universities, journals, and other organizations

Big boost in drug discovery: New use for stem cells identifies a promising way to target ALS

Date:
April 18, 2013
Source:
Harvard University
Summary:
Using a new stem-cell based drug screening technology with the potential to reinvent and greatly reduce the cost of the way new pharmaceuticals are developed, researchers have found a compound more effective in protecting the neurons killed in amyotrophic lateral sclerosis -- Lou Gehrig's disease -- than two drugs that failed in human clinical trials after hundreds of millions of dollars had been invested in them.

The c-Jun-mediated cell death pathway (marked by red nuclei that are positive for phospho-cjun) is activated in stem cell-derived motor neurons (green) exposed to trophic factor withdrawal (upper left panel). C-Jun activation and cell death are blocked by kenpaullone, an inhibitor GSK-3 and HGK (MAP4K4) kinases (lower right panel; kenpaullone structure superimposed).
Credit: Cell Stem Cell, Yang et al.

Using a new, stem cell-based, drug-screening technology that could reinvent and greatly reduce the cost of developing pharmaceuticals, researchers at the Harvard Stem Cell Institute (HSCI) have found a compound that is more effective in protecting the neurons killed in amyotrophic lateral sclerosis (ALS) than are two drugs that failed in human clinical trials after large sums were invested in them.

The new screening technique developed by Lee Rubin, a member of HSCI's executive committee and a professor in Harvard's Department of Stem Cell and Regenerative Biology (SCRB), had predicted that the two drugs that eventually failed in the third and final stage of human testing would do just that.

"It's a deep, dark secret of drug discovery that very few drugs have been tested on human-diseased cells before being tested in a live person," said Rubin, who heads HSCI's program in translational medicine. "We were interested in the notion that we can use stem cells to correct that situation."

Rubin's model is built on an earlier proof of concept developed by HSCI principal faculty member Kevin Eggan, who demonstrated that it was possible to move a neuron-based disease into a laboratory dish using stem cells carrying the genes of patients with the disease.

In a paper published today in the journal Cell Stem Cell, Rubin laid out how he and his colleagues applied their new method of stem cell-based drug discovery to ALS, also known as Lou Gehrig's disease. The illness is associated with the progressive death of motor neurons, which pass information between the brain and the muscles. As cells die, people with ALS experience weakness in their limbs, followed by rapid paralysis and respiratory failure. The disease typically strikes later in life. Ten percent of cases are genetically predisposed, but for most patients there is no known trigger.

Rubin's lab began by studying the disease in mice, growing billions of motor neurons from mouse embryonic stem cells, half normal and half with a genetic mutation known to cause ALS. Investigators starved the cells of nutrients and then screened 5,000 druglike molecules to find any that would keep the motor neurons alive.

Several hits were identified, but the molecule that best prolonged the life of both normal and ALS motor neurons was kenpaullone, previously known for blocking the action of an enzyme (GSK-3) that switches on and off several cellular processes, including cell growth and death. "Shockingly, this molecule keeps cells alive better than the standard culture medium that everybody keeps motor neurons in," Rubin said.

Kenpaullone proved effective in several follow-up experiments that put mouse motor neurons in situations of certain death. Neuron survival increased in the presence of the molecule whether the cells were programmed to die or were placed in a toxic environment.

After further investigation, Rubin's lab discovered that kenpaullone's potency came from its ability also to inhibit HGK, an enzyme that sets off a chain of reactions that leads to motor neuron death. This enzyme was not previously known to be important in motor neurons or associated with ALS, marking the discovery of a new drug target for the disease.

"I think that stem cell screens will discover new compounds that have never been discovered before by other methods," Rubin said. "I'm excited to think that someday one of them might actually be good enough to go into the clinic."

To find out if kenpaullone worked in diseased human cells, Rubin's lab exposed patient motor neurons and motor neurons grown from human embryonic stem cells to the molecule, as well as two drugs that did well in mice but failed in phase III human clinical trials for ALS. Once again, kenpaullone increased the rate of neuron survival, while one drug saw little response, and the other drug failed to keep any cells alive.

According to Rubin, before kenpaullone could be used as a drug, it would need a substantial molecular makeover to make it better able to target cells and find its way into the spinal cord so it can access motor neurons.

"This is kind of a proof of principle on the do-ability of the whole thing," he said. "I think it's possible to use this method to discover new drug targets and to prevalidate compounds on real human disease cells before putting them in the clinic."

Rubin's next steps will be to continue searching for better druglike compounds that can inhibit HGK and thus enhance motor neuron survival. He believes that the new information that comes out of this research will be useful to academia and the pharmaceutical industry.

"These kinds of exploratory screens are hard to fund, so being part of the HSCI" -- which provided some of the funding -- "has been absolutely essential," Rubin said.

Those working on the finding included Clifford Woolf, HSCI nervous system diseases program leader, and postdoctoral students Brian Wainger, Miranda Yang, Shailesh Gupta, Kevin Kim, Berit Powers, and Antonio Cerqueira.

The work was also funded by the New York Stem Cell Foundation and the ALS Association.


Story Source:

The above story is based on materials provided by Harvard University. Note: Materials may be edited for content and length.


Journal Reference:

  1. Yin M. Yang, Shailesh K. Gupta, Kevin J. Kim, Berit E. Powers, Antonio Cerqueira, Brian J. Wainger, Hien D. Ngo, Kathryn A. Rosowski, Pamela A. Schein, Courtney A. Ackeifi, Anthony C. Arvanites, Lance S. Davidow, Clifford J. Woolf, Lee L. Rubin. A Small Molecule Screen in Stem-Cell-Derived Motor Neurons Identifies a Kinase Inhibitor as a Candidate Therapeutic for ALS. Cell Stem Cell, 2013; DOI: 10.1016/j.stem.2013.04.003

Cite This Page:

Harvard University. "Big boost in drug discovery: New use for stem cells identifies a promising way to target ALS." ScienceDaily. ScienceDaily, 18 April 2013. <www.sciencedaily.com/releases/2013/04/130418124901.htm>.
Harvard University. (2013, April 18). Big boost in drug discovery: New use for stem cells identifies a promising way to target ALS. ScienceDaily. Retrieved July 28, 2014 from www.sciencedaily.com/releases/2013/04/130418124901.htm
Harvard University. "Big boost in drug discovery: New use for stem cells identifies a promising way to target ALS." ScienceDaily. www.sciencedaily.com/releases/2013/04/130418124901.htm (accessed July 28, 2014).

Share This




More Health & Medicine News

Monday, July 28, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Deadly Ebola Virus Threatens West Africa

Deadly Ebola Virus Threatens West Africa

AP (July 28, 2014) — West African nations and international health organizations are working to contain the largest Ebola outbreak in history. It's one of the deadliest diseases known to man, but the CDC says it's unlikely to spread in the U.S. (July 28) Video provided by AP
Powered by NewsLook.com
$15B Deal on Vets' Health Care Reached

$15B Deal on Vets' Health Care Reached

AP (July 28, 2014) — A bipartisan deal to improve veterans health care would authorize at least $15 billion in emergency spending to fix a veterans program scandalized by long patient wait times and falsified records. (July 28) Video provided by AP
Powered by NewsLook.com
Two Americans Contract Ebola in Liberia

Two Americans Contract Ebola in Liberia

Reuters - US Online Video (July 28, 2014) — Two American aid workers in Liberia test positive for Ebola while working to combat the deadliest outbreak of the virus ever. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
Traditional African Dishes Teach Healthy Eating

Traditional African Dishes Teach Healthy Eating

AP (July 28, 2014) — Classes are being offered nationwide to encourage African Americans to learn about cooking fresh foods based on traditional African cuisine. The program is trying to combat obesity, heart disease and other ailments often linked to diet. (July 28) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins