UGA researchers receive NIH contract to create a stem cell-based drug assay for SMA

December 14, 2004

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 number one genetic killer of children under the age of two.

The subcontract was awarded through the Spinal Muscular Atrophy (SMA) Project, a model translation program established by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health, to accelerate the process of developing safe and effective treatment of SMA.

The goal of the SMA Project is to identify and complete preclinical research and development of 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 that this will be the first use of human embryonic stem cells in human medicine. 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 and one in 6,000 babies is born with the disease. Of those children diagnosed before age two, 50 percent 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 the development and function of all of the body's motor neurons. In individuals 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 are not enough to keep the neurons in the spinal cord from degenerating.

Transgenic mouse models, developed to study SMN function, have been informative, said Stice. 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," he 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 by former UGA doctoral student Soo Jung Shen using NIH-approved embryonic stem cell lines owned and distributed by BresaGen, a private research company located in Athens. The cell culture-based systems will be designed to test the ability of candidate drugs 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," said Terns.

Outside collaborators providing their scientific expertise to the project include Alan and Elizabeth Davis in the department of pediatrics at Baylor College of Medicine and Jianhua Zhou in the department of medicine at the University of Massachusetts Medical School.

"The development of an in vitro process should speed up the search for compounds and drugs that can alleviate SMA as well as provide a model for developing drug screening assays for other neurological diseases, such as Parkinson's and Lou Gehrig's disease," said Stice.

University of Georgia

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