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.)