Drug therapy can extend survival and improve movement in a mouse model of spinal muscular atrophy (SMA), new research shows. The study, carried out at the NIH's National Institute of Neurological Disorders and Stroke (NINDS), suggests that similar drugs might one day be useful for treating human SMA.

"This study shows that treatment can be effective when started after the disease appears," says Kenneth H Fischbeck, MD, of the NINDS, who helped lead the new study. The finding is important because most children with SMA are diagnosed after symptoms of the disease become obvious, he adds. The report appears in the February 22, 2007, advance online publication of "The Journal of Clinical Investigation".

SMA is the most common severe hereditary neurological disease of childhood, affecting one in every 8,000-10,000 children. Babies with the most common form of the disease, called SMA type I, develop symptoms before birth or in the first few months of life and have severe muscle weakness that makes it difficult for them to breathe, eat, and move. They usually die by age two. Other forms of SMA are not as severe, but still cause significant disability. While some symptoms of SMA can be alleviated, there is currently no treatment that can change the course of the disease.

SMA is caused by mutations in a gene called SMN1. Investigators studying the genetics of SMA have found that there is another gene, called SMN2, on the same chromosome. 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 are searching for drugs that can increase the amount of normal protein produced by this gene.

The new study, directed by Dr Fischbeck's colleague Charlotte J Sumner, MD, at NINDS, tested a drug called trichostatin A (TSA) that is in a class of drugs called histone deacetylase (HDAC) inhibitors. These drugs increase the activity of certain genes in the body.

Previous studies have shown that HDAC inhibitors can increase the amount of SMN2 expression in cultured cells and that treating pregnant mice with an HDAC inhibitor can increase the survival of their babies with SMA.

Preliminary clinical trials are now underway to test several HDAC inhibitors in children who have SMA. However, the drugs in those clinical trials are weak HDAC inhibitors with other biological effects that may limit their usefulness for treating this disease. More importantly, none of the previous studies has demonstrated that HDAC inhibitors can extend survival when delivered after symptoms appeared.

In the new study, the investigators tested TSA, which is a potent HDAC inhibitor, in cells from SMA patients and in a mouse model of SMA. They found that the drug increased the amount of SMN2 gene activity in both the cultured cells and the mouse model.

Next, the researchers gave daily injections of TSA to the SMA mice, starting when the mice were 5 days old. By that time, the mice showed clear symptoms of disease: they were significantly underweight and they had a markedly impaired righting reflex, or ability to get on their feet after being placed on their backs. The treated mice lived 19 per cent longer, on average, than mice that did not receive TSA. About three-fourths of the treated mice had improved survival compared to control mice. The other fourth showed no improvement.

The treated mice had less weight loss and better righting reflexes, walking ability, and forelimb grip strength than mice that did not receive TSA. Examination showed that the TSA-treated mice also had larger neurons in the spinal cord, thicker muscle fibers, and more muscle mass than untreated mice.

"This is a proof-of-concept experiment," says Dr Sumner. "It clearly demonstrates that this treatment can ameliorate the disease in mice. "While the results are exciting, there are still no studies that have proven the effectiveness of HDAC inhibitors in humans, she cautions.

The investigators are now testing whether treatment with TSA earlier in the disease process will work better than the delayed treatment in this study. They also plan to test other HDAC inhibitors in mice and to study exactly how the drugs influence the disease process. While TSA is expensive to produce and it is not approved for clinical use, similar drugs being developed to treat cancer and other diseases may be useful for treating SMA, Dr Sumner says.