Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A Novel Human Stem Cell-based Model of ALS Opens Doors for Rapid Drug Screening

05.12.2008
Long thought of as mere bystanders, astrocytes are crucial for the survival and well-being of motor neurons, which control voluntary muscle movements. In fact, defective astrocytes can lay waste to motor neurons and are the main suspects in the muscle-wasting disease amyotrophic lateral sclerosis (ALS).

To get to the root of this complicated relationship, researchers from the Salk Institute for Biological Studies for the very first time established a human embryonic stem cell (hESC)-based system for modeling ALS. Their study confirmed that dysfunctional human astrocytes turn against their charges and kill off healthy motor neurons. But more importantly, treating the cultured cells with apocynin, a powerful anti-oxidant, staved off motor neuron death caused by malfunctioning astrocytes.

Their findings, which appear in the Dec. 4 issue of the journal Cell Stem Cell, provide new insight into the toxic pathways that contribute to the demise of motor neurons in ALS and open up new possibilities for drug-screening experiments using human ALS in vitro models, as well as clinical interventions using astrocyte-based cell therapies.

“A variety of drugs that had demonstrated significant efficacy in mouse models didn’t keep their promise in both preclinical and clinical trials,” says Fred H. Gage, Ph.D., a professor in the Laboratory for Genetics, who led the study. In fact, just one drug—riluzole— has been approved by the FDA to treat ALS, and it only slows the course of the disease by two months.

“There is an urgent need for new ALS models that have the potential to translate into clinical trials and that could, at a minimum, be used in conjunction with the murine models to verify drugs and drug targets,” says Gage.

ALS, also known as Lou Gehrig’s disease, was named after the legendary New York Yankee slugger who lent his name to the mysterious illness over 60 years ago. Usually fatal, the neurodegenerative disease attacks motor neurons controlling voluntary movement, leading to progressive paralysis and muscle atrophy.

Although ALS was first classified as a disease over 140 years ago, there are still few clues as to its cause. An important step toward understanding the disease came when scientists discovered that ALS can be induced by inherited mutations in the gene encoding the SOD1 enzyme, short for superoxide dismutase 1. This enzyme protects the body from damage caused by free radicals, highly reactive molecules produced by cells during normal metabolism.

Spinal motor neurons express high levels of SOD1, which many originally thought might explain their selective vulnerability. But soon, mouse experiments revealed that motor neuron degeneration is not necessarily associated with the expression of defective SOD1 in the motor neurons per se but rather with its expression in a critical number of neighboring support cells.

Since most treatments that worked in ALS mouse models didn’t live up to expectations in preclinical and clinical trials, postdoctoral researcher and first author M. Carol Marchetto, Ph.D., looked for an alternative: “Transgenic mice containing the human mutated forms of SOD1 have been very useful to study the disease onset and progression. But we felt that cell culture models using both human neurons and astrocytes could potentially be very useful for drug screening and, to some extent, cell replacement therapies.”

To uncover the contribution of astrocytes to human motor neuron degeneration, Marchetto first coaxed hESCs to differentiate into motor neurons through a series of physical manipulations and exposure to a number of growth factors. When she co-cultured these cells with human astrocytes expressing a mutated form of SOD1, the number of motor neurons alive in the Petri dish plummeted. “In the presence of the mutation, the astrocytes activated an inflammatory response and started producing reactive oxygen species, a hallmark of ALS,” says Marchetto.

When she treated these cells with known antioxidants such as apocynin, which is found in many plants, epicatechin, one of the beneficial ingredients in green tea and chocolate, or alpha-lipoic acid, which is produced by the body, the percentage of astrocytes churning out harmful reactive oxygen species decreased significantly. Not only that, when she treated motor neurons cultured in the presence of mutant astrocytes, apocynin—the only one tested in a co-culture experiment—helped motor neurons withstand their no-longer-supportive environment.

“We believe that we can use this system as a rapid drug screening test for oxidative damage to identify the best candidates for subsequent long-term co-culture experiments,” says Marchetto.

While research on the effects of the SOD1 gene mutation is providing important clues about the possible causes of motor neuron death, only a small fraction of all ALS cases are actually due to the mutation; other as yet unidentified genetic causes clearly exist.

“The rapid advances in induced pluripotent stem cell technology will soon allow us to generate patient-specific stem cells that can be used in our co-culture assay to gain new insight into the different causes of ALS,” says Gage.

For information on the commercialization of this technology, please contact Mike White at 858-453-4100, x 1703 (mwhite@salk.edu) in of the Salk Office of Technology Management and Development.

This study was funded by Project ALS, the Dana and Christopher Reeve Foundation, the California Institute for Regenerative Medicine, the Lookout Fund, and the National Institutes of Health.

Researchers who also contributed to the work include postdoctoral researchers Alysson R. Muotri, Ph.D., and Yangling Mu, Ph.D., in the Gage laboratory, postdoctoral researcher Alan M. Smith, Ph.D., and assistant professor Gabriela G. Cezar, Ph.D., both at the University of Wisconsin-Madison, Madison.

Gina Kirchweger | Newswise Science News
Further information:
http://www.salk.edu

More articles from Life Sciences:

nachricht Water world
20.11.2017 | Washington University in St. Louis

nachricht Carefully crafted light pulses control neuron activity
20.11.2017 | University of Illinois at Urbana-Champaign

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

Im Focus: Wrinkles give heat a jolt in pillared graphene

Rice University researchers test 3-D carbon nanostructures' thermal transport abilities

Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Antarctic landscape insights keep ice loss forecasts on the radar

20.11.2017 | Earth Sciences

Filling the gap: High-latitude volcanic eruptions also have global impact

20.11.2017 | Earth Sciences

Water world

20.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>