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Salk Team Develops Novel hESC ALS Model as Harvard Sheds New Light on Mutant SOD1 Gene

Researchers at the Salk Institute this week published a paper describing how they developed a novel in vitro model of amyotrophic lateral sclerosis that could potentially replace the use of mouse models to study the fatal neurodegenerative disease.
Separately, researchers at Harvard University have developed a method for the large-scale production of human embryonic stem cell-derived human motor neurons, which they used in coculture experiments to determine if they were sensitive to the toxic, non-cell-autonomous effect of SOD1-mutated glial cells.
Together, these studies provide new insight into the pathways that contribute to the demise of motor neurons in ALS, and could lead to new drug-screening studies that use human in vitro models for a disease previously modeled only in mice.
“I think that what is exciting about these publications is that they try to address human systems, whereas most of the published work has been in mouse-derived stem cells and mouse-derived motor neurons,” said Lucie Bruijn, senior vice president of research and development for the ALS Association, a nonprofit patient-advocacy group unaffiliated with either study.
She added that it is interesting these studies look at similar pathways and inflammatory processes that are studies in mouse models, but it is more efficient to use human-based in vitro models to test drugs.
Also, these studies describe interesting approaches to developing new systems for drug screening that could eventually be used to shed additional light on the mechanisms of the disease, said Bruijn.
Both groups published their findings this week in the December issue of Cell Stem Cell. Salk’s paper appears here and Harvard’s research appears here.
According to David Fischer, director of biology for the target-discovery compound-screening company BioFocus DPI, the two studies are novel because they combine in a single assay human embryonic stem cell-derived motor neurons and the glial cells.

“[W]hat is exciting about these publications is that they try to address human systems, whereas most of the published work has been in mouse-derived stem cells and mouse-derived motor neurons.”

Both studies relied on similar approaches to generate in vitro models for ALS, according to the papers. Common in vitro models for ALS either address the biochemical deficits of the SOD1 protein, which is a causative factor in a small percentage of ALS patients, or they investigate the sensitivity of motor neurons — those brain cells that degenerate in ALS — in isolated cultures, Fischer said. 
Both research groups used wild-type hESC-derived motor neurons as a read out to show that glia expressing the mutant SOD1 protein exert a toxic effect on motor neurons in these cultures. Fisher, who did not participate in either study, said he found it interesting that both groups identified similar yet different toxic mediators of the inflammatory response that could provide an entry point for the development of novel therapeutics.
The Salk investigators found that mutated SOD1 murine astrocytes could activate NOX2, which stimulates the production of reactive oxygen species in SOD1 mutation-expressing glia, and that effect could be reversed by the NOX2 inhibitor apocynin.
The Harvard researchers, meantime, found that when they added prostaglandin D2 to motor neurons co-cultured with normal glia, motor neuron survival was significantly reduced. However, an inhibitor of prostaglandin signaling partially rescued motor neuron loss.
No Mousing Around
There has been no paper published that describes the co-culture of human glia and hESC-derived motor neurons for many reasons, ALS Association’s Bruijn said. The field of human embryonic stem cell research has been improving, but it is not so easy to manipulate motor neuron-derived systems.
For example, “If you compare mouse development to human development, it’s a totally different timeframe,” she said. It takes longer to get to the point where one can derive motor neurons in human ESC cultures than in mouse ESC cultures.
“It is not as if you can say, ‘We will use exactly the same conditions as in a mouse to get this happening in humans.’”
In addition, it has only been a year since the DiGiorgio and Nagai mouse studies which demonstrated a similar effect of SOD1-mutated glia on mouse motor neurons were published, said Bruijn. “So it is not as if it is that far apart.”  
The development of similar, more complex assays involving primary cells, hESC-derived cell types, and co-cultures of different cell types is believed to increase the clinical relevance of in vitro screening campaigns for complex diseases such as ALS, said BioFocus DPI’s Fischer. These developments are “desperately” needed, not only by patients with ALS but also by patients with more common diseases such as Alzheimer's disease, he said.
Only one drug, Aventis Pharmaceuticals’ Rilutek, is currently approved in the US, but it only slows the course of the disease by approximately two months. Bruijn said that several reasons exist for this dearth of effective treatments for ALS.
It is a relatively rare disorder, so the pharmaceutical industry has not focused on finding effective treatments. According to the ALS Association, approximately 5,600 people in the US are diagnosed with ALS each year, and it is estimated that as many as 30,000 people in the country may have the disease at any given time.
Because it is a complex disease, “we really do not know the majority of causes” of it.
It is also a very difficult disease to treat, said Bruijn. Drugs for central nervous system diseases, in particular ALS, are very few and far between because of the difficulty of developing an agent that can cross the blood-brain barrier.
In addition, many patients with ALS die within 2 to 5 years, so the cumulative number of people with the disease is small.  

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