Drug provides glimmer of hope for children suffering fatal genetic disease

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.

"It was devastating to me and to the parents to see these hopeless kids dying in front of us, and we couldn't do a thing about it. I decided to investigate the disease, but I never expected it would go this far," said Wang, who is the director of Lucile Packard Children's Hospital neuromuscular disorders clinic and an associate professor of neurology at the School of Medicine.

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.

It's the first glimmer of hope on what has been a very dark horizon for the families of children with SMA. He's currently conducting a clinical trial to test whether the treatment can slow or halt the progression of the disease in affected children.

The genetics of SMA are complicated. About 1 in 10,000 children are born missing a gene necessary to maintain the spinal nerves that control movement. Without this gene, known as spinal motor neuron 1, the nerves begin to degenerate. Severely affected infants have little muscle control and may have trouble breathing. They can't sit up or roll over, and usually die before their second birthday. Older infants and adults diagnosed later in life are usually less affected, and exhibit varying degrees of weakness.

The key to these differences in severity lies in the fact that we all happen to have two versions of this gene: SMN1 and SMN2. Unfortunately, SMN2 is an imperfect understudy. Although the two versions diverge by only a single nucleotide, SMN2 is much less efficient than SMN1 at generating the necessary protein.

SMN2's less-than-stellar performance as a protein maker stems from a mutation that causes the cell to leave out one essential chunk, or exon, when generating the RNA that is used as the protein template. But about 10 percent of the time the cell accidentally includes the exon and generates enough functional protein to keep the person alive, if only for a short time. Still, every little bit helps: less-affected SMA patients have more copies of SMN2 while those who are more severely affected have fewer copies. Wang and his colleagues wanted to improve those odds.

They knew that some compounds can increase the expression of the protein in cells from people with the disease, but all of these candidates had drawbacks: either they were difficult to administer orally, they were toxic, or they just hadn't been studied well enough yet to qualify for use in humans. There remained one possible compound to try—a drug called hydroxyurea, which can increase the expression of other genes, including hemoglobin. In fact, hydroxyurea is so successful that it's currently used as an approved treatment for blood diseases like sickle cell anemia and thalassemia.

The researchers found that hydroxyurea treatment significantly increased the levels of SMN protein in cells from SMA patients with all levels of disease severity. They speculate that, rather than just increasing the overall pool of SMN2 RNA, hydroxyurea instead somehow spurs the inclusion of the missing exon from already existing RNA.

"We don't yet have a lot of evidence of how it works," says Wang. "Hydroxyurea may increase the expression of other transcription factors, which may in turn encourage the cell to ignore the mutation in the SMN2 gene and cause it to function more like SMN1." In the future, the scientists plan to investigate exactly which factors might be involved.

In the meantime, however, hydroxyurea's long therapeutic track record and ease of use allowed the researchers to move rapidly into clinical trials. In 2004 they began enrolling children from around the country into two clinical trials: one for the most severe form and one for the second-most-severely affected. They hope to have data sometime in 2006. Wang and his colleagues aren't the only ones who are anxiously awaiting the results.

"This data is first hope for the SMA community that there may be an effective drug that can reverse the disease process," says Wang. "Until now the disease has been unrelenting in its progression."

The research was funded by the Spinal Muscular Atrophy Foundation and the Muscular Dystrophy Association.