Published on 12/16/04

Scientists making stem-cell-based SMA drug test

By Rebecca Ayer
University of Georgia

Athens, Ga. – Researchers at the University of Georgia have been awarded a $425,598 subcontract to develop a human embryonic stem-cell–derived test for screening drugs capable of treating spinal muscular atrophy, the No. 1 genetic killer of children under 2 years old.

The subcontract was awarded through the Spinal Muscular Atrophy Project to speed up the process of developing safe and effective treatment of SMA.

The SMA Project is a model translation program established by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. Its goal is to identify and complete preclinical research and develop candidate therapeutics for treating SMA by late 2007.

The UGA team hopes to have the first assay ready in one year.

"All the talk surrounding stem cell research has focused on cell therapy," said Steven Stice, one of UGA's Georgia Research Alliance Eminent Scholars and the project's principal investigator.

"We hope this will be the first use of human embryonic stem cells in human medicine," Stice said. "Our goal is to have an immediate impact on health issues through better ways of identifying promising drug therapies for diseases like SMA."

Spinal muscular atrophy is a group of inherited and often fatal diseases that destroys the nerves necessary for voluntary muscle movement, such as crawling, walking, head and neck control and even swallowing.

According to the NIH, one in every 40 people is a genetic carrier of the disease. One in 6,000 babies is born with it. And of the children diagnosed before age 2, half will die before their second birthday.

SMA is caused by a defect in the survival motor neuron gene 1 (SMN1), which produces a protein necessary for all of the body's motor neurons to develop and function.

In people with SMA, limited amounts of SMN protein are provided by a second SMN gene (SMN2) and allow for the correct functioning of most of the body's cells.

However, the reduced protein levels produced by SMN2 aren't enough to keep the neurons in the spinal cord from degenerating.

Transgenic mouse models developed to study SMN function have been informative, Stice said. However, typical model systems, such as the mouse, possess only one SMN gene. And research has found that the initial survival of human SMA patients depends on protein produced by the SMN2 gene, found only in humans.

"The unique sensitivity of spinal motor neurons and configuration of SMN genes in humans make it essential for us to create a better model to study the disease," Stice said. "And the best model would be a human one."

Stice and his group will establish two different, but complementary, human motor neuron systems using mixed motor neuron cultures derived using NIH-approved embryonic stem cell lines owned and distributed by BresaGen, a private research company in Athens.

The cell-culture–based systems will be designed to test candidate drugs' ability to increase SMN protein levels.

"We have good candidate drugs from studies in other systems," said Michael Terns, associate professor of biochemistry and molecular biology at UGA. "In addition, there are libraries of compounds available for testing to see if protein concentrations go up without having to know the mechanism behind it."

Michael and Rebecca Terns, both advisors on the SMA Project contract, have been studying the molecular functions of SMN1 since their laboratory first cloned the gene in 1996.

The Terns recently received a $300,000 supplement to their existing grant from the NIH to specifically examine the function of SMN in motor neurons.

"What our lab is trying to understand is why only spinal motor neurons are affected by a mutation in SMN when the gene is involved in mechanisms required for all cell functioning," Terns said.

(Rebecca Ayer is an information specialist with the University of Georgia Biomedical and Health Sciences Institute.)

Rebecca Ayer is an information specialist with the University of Georgia Biomedical and Health Sciences Institute.