Liang WC, Yuo CY, Chang JG, Chen YC, Chang YF, Wang HY, Ju YH, Chiou SS, Jong YJ, Department of Pediatrics, Kaohsiung Medical University Hospital, Taiwan

BACKGROUND: Spinal muscular atrophy (SMA) is a degenerative motor neuron disease caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene. Effective treatment for SMA is unavailable at present. The aim of this study was to investigate the effect of hydroxyurea (HU) in SMA cells and patients.

MATERIALS AND METHODS: Fifteen SMA lymphoid and three fibroblast cell lines, 2 from SMA patients and 1 control, were treated with HU at different concentrations, and 33 patients (types II, III) randomized into three groups on different HU dosage, 20, 30, 40 mg/kg/day, were treated for 8 weeks and followed up for another drug-free 8 weeks. The effect of HU on SMN2 gene expression and clinical manifestations was evaluated.

RESULTS: After treatment, in vitro, full-length mRNA level and gems number increased significantly, and hnRNP A1 protein decreased. In vivo, there were slight increases in muscle strength scores at 4 weeks and full-length SMN mRNA at 8 weeks in 30 mg/kg/day subgroup.

CONCLUSIONS: Treating with HU enhanced SMN2 gene expression in SMA cells and showed slight trend towards improvement in some clinical outcome measures in SMA patients which suggests HU may be safe to use in SMA patients but larger randomized, placebo-controlled, double-blind trials are needed to further investigate its efficacy.
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When Elizabeth Lee Hallam was born on Sept. 29, 2003, she was a textbook example of the perfect baby. But by 8 months of age, she was battling a fatal genetic disease her family had never heard of. Elizabeth was diagnosed with the most acute form of spinal muscular atrophy, a motor neuron disorder similar to Lou Gehrig’s disease that afflicts one in 6,000 babies. With no cure or treatment, the doctor predicted Elizabeth – like 95 percent of all SMA babies – would not live more than two years.

“I screamed when we got the news,” said her grandmother, Jeanna Huette, 48. “I could not understand how such a beautiful child could just die. I cried for a few more days … and then I knew I had to save her.” As Elizabeth approaches her third birthday, she cannot sit, stand, crawl or walk and relies on machines to swallow, get nourishment and even cough. But she is alive and improving.

Her family enrolled Elizabeth in a trial designed to test the safety and effectiveness of the drug hydroxyurea against SMA. It is one of only a few clinical studies on the disease approved by the Food and Drug Administration and is run by Dr. Ching Wang, a scientist affiliated with Stanford University who has made conquering the disease his life’s work.
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In June the 10th Annual Spinal Muscular Atrophy Research Group Meeting was held in Montreal, Canada. Over 160 researchers and clinicians attended. Scientific sessions were held on the following topics: Clinical Trials, Outcome Measures, Stem Cell Therapies, SMN Functions, and Drug Discovery Programs. Over 80 presentations were given. A detailed overview of each session is provided below.

We would like to take this opportunity to highlight several particularly relevant research developments separately. These include the development of novel clinical trial outcome measures for both Type I and ambulatory Type III patients, which will allow future trials to enrol additional SMA patient types. On the basic research front, one the most interesting highlights was new data presented by multiple labs indicating that SMN has a specific function in neurons and that the role of SMN in the cell body is likely different than its role in motor axons. This is important because delineating and understanding the importance of the specific role of SMN in axons will facilitate more strategic design of drug discovery screens. Drs. Hans Keirstead and Doug Kerr also gave exciting talks on stem cell therapies for SMA. Dr. Kerr showed that mice motor neurons derived from mouse stem cells send axons out of the spinal column into the periphery when injected into the spinal cord. These motor axons can form functional connections on muscles, which provided clinical improvement in mice with motor neuron disease. Moreover, Dr. Keirstead reported good progress on developing stem cell-derived motor neurons for human trials. Finally, there were a number of talks focusing on drug discovery efforts to find novel small molecule therapies for SMA. Talks on this topic were given by representatives of the labs of deCODE Chemistry, Christina Brahe, Brunhilde Wirth, Brent Stockwell, the NINDS SMA project, and Trophos. The initiative on up-regulating SMN levels in SMA that is closest to the clinic was given by deCODE Chemistry.
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Ching Wang, MD, PhD, didn’t sign up for his pediatric neurology residency in 1990 to watch children die. But, as in nearly any medical specialty, there are some fatal diseases for which no effective treatment exists. Frustrated after delivering grim news to one too many sets of parents, Wang vowed to do something. He went back into the lab to learn more about spinal muscular atrophy, or SMA, and has spent the last 15 years researching the condition, which is the most common genetic disorder responsible for the deaths of children under two. . . .

Wang has been involved in identifying the cause of the disorder, cloning the responsible gene and modifying its expression. Now he’s the senior author on a research article that was published in the August issue of the Annals of Neurology that shows the genetic defect can be overcome in human cells with the condition.
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Spinal muscular atrophy (SMA) is a motor neuron disease caused by dysfunction of the survival motor neuron (SMN) gene. Human SMN gene is present in duplicated copies: SMN1 and SMN2. More than 95% of patients with SMA lack a functional SMN1 but retain at least one copy of SMN2. Unlike SMN1, SMN2 is primarily transcribed into truncated messenger RNA and produces low levels of SMN protein. We tested a therapeutic strategy by treating cultured lymphocytes from patients with SMA with hydroxyurea to modify SMN2 gene expression and to increase the production of SMN protein. Twenty lymphoblastoid cell lines (15 SMA and 5 control lines) were treated with hydroxyurea at 5 concentrations (0.5, 5, 50, 500, and 5,000 microg/ml) and 3 time points (24, 48, and 72 hours). SMN2 gene copy numbers were determined using real-time quantitative polymerase chain reaction. Hydroxyurea treatment resulted in a time-related and dose-dependent increase in the ratio of full-length to truncated SMN messenger RNA. SMN protein levels and intranuclear gems also were significantly increased in these hydroxyurea-treated cells. The SMN2 gene copy number correlated inversely with the SMA phenotypic severity. This study provides the first evidence for a therapeutic indication of hydroxyurea in SMA.
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