Science Editor

In a paper in the Feb. 22, 2007 issue of The Journal of Clinical Investigation, researchers from the National Institute of Neurological Diseases and Stroke and the Institute of Cell Biology in Rome reported new findings relating to the potential of using newer, more potent HDAC inhibitors to combat the consequences of the spinal muscular atrophy.

Meanwhile, Atlanta-based Tikvah Therapeutics is trying to improve the odds for HDAC inhibitors via another approach - basically, make them taste better.

Spinal muscular atrophy is a neurodegenerative disease that is caused by mutations in the SMN1 (survival motor neuron 1) gene. Motor neurons may not develop properly and degenerate without the SMN1 protein, which in turn leads to muscle weakness.

The SMN gene is somewhat unusual in that humans - and only humans - have two copies of it. Disease occurs when SMN1 is mutated and does not make functional protein; but its severity is greatly influenced by how much functional protein SMN2 manages to turn out.

Unfortunately, the SMN2 gene makes a useless protein most of the time. Because of a mutation in its regulatory sequences, Charlotte Sumner, a researcher at the NINDS and the senior author of the JCI paper, explained that "most RNAs made from SMN2 lack an exon." Without that exon, the protein is too unstable to perform its normal cellular functions.

However, "some of the time, [SMN2] makes a full-length RNA, and that RNA goes on to produce a full-length protein, which is functional," Sumner said. And because the truncated protein is not harmful, the more SMN2, the better. Studies in both mice and patients have shown that the more copies of SMN2, the milder the disease tends to be. For the same reason, kicking SMN2 transcription into high gear "should prove beneficial" in SMA patients.

Sumner and her colleagues used a mouse model to test whether activating SMN2 through the HDAC inhibitor TSA could alleviate their symptoms. The scientists tested the drug in cells from SMA patients and in a mouse model of SMA. In both models, they found that the drug increased SMN2 gene activity.

The researchers then gave daily injections of TSA to SMA mice, starting when the animals already showed clear symptoms of disease. Sumner said they wanted to treat the mice "at a time that is relevant for patients, that is, when the mouse is already sick." The TSA-treated mice lived about 20 percent longer, than untreated controls.

Currently, no HDAC inhibitors are approved for the treatment of SMA. Sumner said that TSA is more specific and potent than some other HDAC inhibitors, which might account for its success.

An older HDAC inhibitor, phenylbutyrate, sometimes is used off-label to treat patients with SMA, and Tikvah is in early Phase II clinical trials with a form of phenylbutyrate to treat SMA.

Tikvah CEO Harold Shlevin provided a forceful reminder that good targets and good drugs are important in leading a horse to water, but sometimes you need extra tricks to get it to drink. "One little-known fact about phenylbutyrate is that is has the world's worst taste," he said. "When you try to feed this to infants and children, they just spit a lot of it out."

Add to that the very high doses of phenylbutyrate that are necessary to achieve a therapeutic effect and any parent will cringe in sympathy at the practicalities of administering the drug to a baby.

Shlevin told BioWorld Today that the company "has licensed patents and technologies that makes the delivery of phenylbutyrate really convenient," both by concentrating the drug more than currently is possible and by masking its taste.

Shlevin said the JCI paper "helps our understanding one more step," and added that the interest of institutions like the NINDS in the area is "encouraging," both because of the medical need and because research into SMA might provide insights that could be applied to other neurodegenerative disorders. He noted, however, that for now there is no way to be sure whether greater specificity portends greater clinical success in the case of HDAC inhibitors. Sometimes, "we don't know enough about the science," he said. "I think the clinical studies will tell us that."

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