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Salk’s system seeks speedy ALS drug screening
January 2009
by Lloyd Dunlap  |  Email the author
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LA JOLLA, Calif.—In work that builds on previous research showing that ALS (also known as Lou Gehrig's disease) transgenic mice expressing mutated SOD1 enjoy better survival, motor and respiratory functions when transplanted with astrocyte precursors, scientists at the Salk Institute have developed a novel human stem cell-based model of ALS they believe can lead to the rapid development of therapies based on motor neuron transplantation.

"If our data can be replicated by other groups and in other models of ALS, it could lead to a therapy to be tried by clinicians," says Dr. M. Carol Marchetto, a post-doctoral researcher at the institute and lead author of the study. Therapies based on astrocyte precursors are likely to be faster than therapies based on motor neuron transplantation, she adds, because astrocytes are easier to grow and to manipulate in vitro.

"However," she notes, "a lot of research has to be done to elucidate the mechanism by which the glia is nurturing the motor neuron. Is it a factor produced by glia? Or does the glia have to make physical contact with the neuron?"

Astrocytes have been previously thought of as "bystanders," but research is now characterizing them as crucial to the survival of motor neurons. To reach this conclusion, the Salk team established a human embryonic stem cell (hESC)-based system for modeling ALS.

Their study went beyond the known fact that ALS can be induced by inherited mutations in the gene encoding the superoxide dismutase 1 (SOD1) enzyme to demonstrate that known antioxidants such as apocynin decrease the percentage of astrocytes churning out harmful free radicals that damage neurons. When co-cultured in the presence of mutant astrocytes, apocynin helped motor neurons withstand the inhospitable environment.

"We believe we can use this system as a rapid drug-screening test for oxidative damage to identify the best candidates for further studies," Marchetto says.

Marchetto notes that induced pluripotent stem cell (iPS) technology may enable scientists to make patient-tailored cells. In ALS, she sees three possibilities. The first would be to make iPS from sporadic and familial ALS cases, differentiate the cells into motor neurons and screen for drugs that increase neuron survival in both case types. iPS cells could also be differentiated into astrocytes and screened for compounds that enhance their supportive role. Most ambitious would be to make iPS cells taken from a patient known to possess a familial ALS mutation, make astrocytes from the patient iPS, cure the mutation in vitro and transplant the "cured" astrocytes back into the patient. DDN
 
Code: E010919

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