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Valproic Acid Shows Promise for Treating Spinal Muscular Atrophy

For release: Wednesday, February 18, 2004

One of the first studies of valproic acid as a potential therapy for spinal muscular atrophy (SMA) shows that, in cultured cells, the drug increases production of a protein that is reduced or missing in people with the disorder. While preliminary, the study suggests that valproic acid or related drugs may be able to halt or even reverse the course of this devastating childhood disease.

The study was led by Kenneth H. Fischbeck, M.D. and Charlotte J. Sumner, M.D., from the National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH). The other researchers were from the NIH's National Institute of Allergy and Infectious Diseases, Ohio State University, and Vertex Pharmaceuticals, Inc. The results are published in the November 2003 issue of the Annals of Neurology .1

"This is an encouraging finding, because it points the way to an approach to treatment for SMA," says Dr. Fischbeck.

The researchers used cultured cells taken from patients with SMA type I, the most devastating form of the disorder. Babies with this form of SMA, also called Werdnig-Hoffman disease, have severe muscle weakness and usually die by age 2. Patients with SMA type II usually begin to show symptoms by 12-18 months of age and may learn to sit but not to stand or walk independently. Their life expectancy varies. Patients with SMA type III (Kugelberg-Welander disease) begin to experience symptoms after 18 months of age. They are usually able to walk and perform most other activities, and they often live into adulthood. All three forms of childhood-onset SMA are linked to mutations in the same gene, called SMN1, which produces a protein by the same name. People with a relatively large amount of SMN1 protein tend to have milder symptoms than those who produce less of the protein.

Investigators studying the genetics of SMA have found that there is another gene called SMN2, which is almost identical to SMN1, on the same chromosome. However, while the normal form of SMN1 produces a full-length functional protein, most of the protein produced by SMN2 is truncated and unable to function. The relatively small amount of normal SMN protein produced by the SMN2 gene can reduce the severity of the disease. Therefore, investigators have begun looking for drugs that can increase the amount of normal protein produced by this gene.

In the new study, the researchers tested valproic acid, a commonly used epilepsy drug, to see if it would increase the amount of normal protein produced by the SMN2 gene. They found that the more drug they gave, the greater the amount of gene activity. The drug also increased production of functional SMN protein by 30 to 50 percent. Another recent study by investigators from Germany found similar results.2

The investigators chose to study valproic acid because it belongs to a class of drugs known as histone deacetylase (HDAC) inhibitors. These drugs increase the activity of certain genes in the body. Previous work has shown that an HDAC inhibitor called sodium butyrate can increase the amount of full-length SMN protein produced by the SMN2 gene. However, sodium butyrate is quickly eliminated from the body and is not well-suited for human use, the investigators say. Valproic acid, on the other hand, is usually well-tolerated and has been used for decades to treat people with epilepsy.

While the results are interesting, it is too soon to know whether valproic acid will have therapeutic effects in humans with SMA, Dr. Sumner cautions. The two recently published studies have shown a potential benefit only in cultured cells. Treatment with valproic acid can lead to liver toxicity, especially in children under 2 years of age, and safe doses of the drug may not be able to increase the amount of SMN protein enough to reduce symptoms of the disease, she adds. Researchers led by Kathryn Swoboda, M.D., at the University of Utah, are now conducting a preliminary clinical trial of valproic acid in children with SMA who are 2 years of age and older in order to determine whether the drug is safe enough for further study in children with this disorder.

Other HDAC inhibitors also may be useful for treating SMA. "Even if this isn't the best drug for SMA, there is still promise for this class of drugs," Dr. Sumner says. Both Dr. Swoboda and an Italian group led by Dr. Christina Brahe of Università  Cattolica del Sacro Cuore in Rome are studying a drug called sodium phenylbutyrate. Such drugs might be able to treat SMA without as many side effects as existing drugs.

The NINDS researchers are now studying various HDAC inhibitors in a mouse model for SMA in order to determine how these drugs work in living animals, Dr. Sumner says. They are also developing a test that will allow them to track the level of SMN protein in patients' blood. The blood test will help investigators monitor whether a drug is working even if they can't see improvements in symptoms during the course of a clinical trial. Other research is needed to determine whether increasing the SMN level will help the disease in humans, and to find out how early treatment must start in order to improve the course and/or symptoms of the disease, she adds.

The NINDS, part of the National Institutes of Health within the U.S. Department of Health and Human Services, is the nation's leading supporter of research on the brain and nervous system.


1 Sumner CJ, Huynh TN, Markowitz JA, Perhac JS, Hill B, Coovert DD, Schussler K, Chen X, Jarecki J, Burghes AHM, Taylor JP, Fischbeck KH. "Valproic acid increases SMN levels in spinal muscular atrophy patient cells." Annals of Neurology , November 2003, Volume 54, No. 5, pp. 647-654.

2 Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H., Bumcke I, Eyupoglu IY, Wirth B. "Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy." Human Molecular Genetics , 2003, Vol. 12, No. 19, pp. 2481-2489.

-By Natalie Frazin


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Last Modified April 16, 2014