Navigation Links
Reinventing drug discovery

Cambridge, MA, April 18, 2013 - 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, Harvard Stem Cell Institute (HSCI) researchers have found a compound more effective in protecting the neurons killed in amyotrophic lateral sclerosis (ALS) 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 new stem cell 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, successfully predicted that the two drugs that eventually failed in the third and final stage of human testing would, in fact, fail.

"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 lays out how he and his colleagues applied their new method of stem cell-based drug discovery to ALS. The disease 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 first 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 five thousand drug-like 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 placed in a toxic environment.

After further investigation, Rubin's lab discovered kenpaullone's potency comes from its ability to also 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 works 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."

In the meantime, Rubin's next steps will be to continue searching for better drug-like 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.


Contact: B. D. Colen
Harvard University

Related medicine news :

1. Scientist awarded $1 million grant to develop tools for hepatitis C treatment discovery
2. Washingtons Life Sciences Discovery Fund awards commercialization grants
3. Discovery could help to develop drugs for organ transplant and cancer patients
4. Feelings of immaturity accompany alcohol misuse into adulthood; discovery could improve treatments
5. H1N1 discovery paves way for universal flu vaccine: UBC research
6. Scientists make breakthrough in bile duct cancer with discovery of new gene mutations
7. Researchers make promising discovery in pursuit of effective lymphoma treatments
8. Discovery suggests new combination therapy strategy for basal-like breast cancers
9. Discovery of Gene May Lead to New Male Contraceptive
10. 5 more pharmaceutical companies join NIH initiative to speed therapeutic discovery
11. Illnesses in Colorado childrens hospital prompts discovery of contaminated alcohol pads
Post Your Comments:
(Date:11/27/2015)... (PRWEB) , ... November 27, 2015 , ... ProSidebar: ... in Final Cut Pro X. With ProSidebar: Fasion, video editors can easily add ... ProSidebar as a minimalist title opener. Utilize presets featuring self-animating drop zones, lines, ...
(Date:11/27/2015)... VVA (PRWEB) , ... November 27, 2015 , ... ... motto of progress through sharing, the 2016 Building Better Radiology Marketing ... The conference will begin on Sunday, March 6, 2016, at Caesars Palace in ...
(Date:11/27/2015)... ... , ... A simply groundbreaking television series, "Voices in America", which is hosted ... array of issues that are presently affecting Americans. Dedicated to providing the world with ... changing the subjects consumers focus on, one episode at a time. , In ...
(Date:11/27/2015)... ... November 27, 2015 , ... Keeping in ... for mental health and wellness consultation, has collaborated with a leading web-based marketplace ... knowledge gap experienced by parents and bring advice from parenting experts within their ...
(Date:11/27/2015)... ... 27, 2015 , ... The men and women on this ... in the country. They have overseen financial turnarounds, shown commitment to their community ... industry as a whole through their advocacy and professional efforts. , Becker's Hospital ...
Breaking Medicine News(10 mins):
(Date:11/26/2015)... , November 26, 2015 ... A new combination approach blends immunotherapy with Bremachlorin-photodynamic therapy ... new combination approach blends immunotherapy with Bremachlorin-photodynamic therapy for ... new combination approach blends immunotherapy with Bremachlorin-photodynamic therapy for ... has found that immunotherapy can be efficiently ...
(Date:11/26/2015)... -- Research and Markets ( ) has ... Horizons and Growth Strategies in the Japanese Therapeutic ... Forecasts, Competitive Intelligence, Emerging Opportunities" report to ... --> This new 247-page report provides ... monitoring market, including emerging tests, technologies, instrumentation, sales ...
(Date:11/26/2015)... DUBLIN , Nov. 26, 2015 Research ... of the "Advanced Wound Care Market by Type ... Ulcers), End User (In-Patient Facility, Out-Patient Facility), and Geography ... offering. --> --> ... the description, definition and forecast of the global advanced ...
Breaking Medicine Technology: