SMA DRUG SEARCH GAINS GROUND

MDA-funded scientists have reported progress toward developing a drug treatment for spinal muscular atrophy (SMA) -- a life-threatening disease that kills muscle-controlling nerve cells (motor neurons) in the spinal cord.

Nearly all cases of SMA are caused by flaws in the SMN1 gene, which encodes a protein called survival motor neuron (SMN). Everyone has a "backup" SMN gene called SMN2, but it produces very low levels of active SMN protein -- not enough to fully substitute for SMN1.

The key difference between SMN1 and SMN2 lies in the way cells handle RNA (the intermediate between genes and proteins). Two years ago, MDA grantees Christian Lorson of Arizona State University in Tempe and Elliot Androphy of New England Medical Center in Boston showed that an essential piece of SMN2 RNA is normally removed, creating a shortened (and mostly nonfunctional) SMN protein.

Still, people with SMA who happen to have extra copies of the SMN2 gene develop a less severe form of the disease (SMA type 2 or 3) and, in mice, a genetically engineered boost of SMN2 can eliminate the disease.

Inspired by those observations, the San Diego-based biotechnology company Aurora Biosciences is screening millions of chemicals to find drugs that might jump-start SMN2. In the meantime, Lorson, Androphy and two other research teams have reported some promising "hits" with smaller screens.

In their MDA-funded screen, Lorson, Androphy and their team attached the SMN2 gene to the gene for jellyfish green fluorescent protein (GFP), and injected the fused SMN2-GFP gene into cells in a petri dish. That allowed them to use a simple color change -- from no color to bright green -- to identify chemicals that stimulated the cells to make full-length SMN2. In the November issue of Gene Therapy, they report that the mineral sodium vanadate turned the cells green, and also increased the level of full-length SMN2 in cells derived from people with SMA.

The other two groups conducted similar screens, starting with cells from those with SMA.

One group found that the antibiotic and anti-cancer drug aclarubicin increased the amount of full-length SMN2. The team, led by Arthur Burghes of Ohio State University in Columbus, presented its findings at the American Society of Human Genetics meeting held in San Diego in October. With support from MDA, Burghes created the mouse model of SMA in the late 1990s.

The other group found similar results with sodium butyrate -- a drug that's been used to treat certain kinds of anemia. When tested on mice, the drug appeared to lessen the severity of SMA, and improved survival in those with mild disease signs similar to SMA types 2 and 3. The group, led by Hung Li of Kaohsiung Medical University in Taiwan, published its findings in the Aug. 14 issue of the Proceedings of the National Academy of Sciences.

Despite the promising results, it's unclear whether any of the chemicals can be used to treat SMA, since each one appears to be harmful in large doses. But researchers say these small screens offer an encouraging look ahead at Aurora's large screen.

Lorson said, "Clearly, there is a huge jump from cultured cells or mice to humans, and controlled clinical trials are essential once any screen is done. Mostly, these [small screens] are great 'proof of principle' experiments in the sense that now we know there are chemicals that can modulate the RNA processing of SMN2."