Using medications to prolong life and improve mobility in mice with spinal muscular atrophy

According to the results of a new study, drug treatment may help prolong life and improve mobility in experimental mice with spinal muscular atrophy (SMA). The study was conducted at the National Institute of Neurological and Stroke Disorders (NINDS) of the National Institutes of Health (NIH) of the United States and hypothesized that future drugs could be similar in the future. will be helpful in treating SMA in humans.

Dr. Kenneth H. Fischbeck of NINDS said: 'This study shows that treatment can be effective if treatment begins after the disease appears.' This finding is important because most children with SMA are diagnosed with the disease forever after symptoms become too obvious. The report of this study was published on the electronic newsletter of The Journal of Clinical Investigation on February 22, 2007 .

SMA is the most common severe hereditary neurological disease in children . One in 8,000-10,000 children has one. Children with the most common form of the disease, called SMA 1, often have symptoms right before birth or in the first few months of life, and often have severe muscle weakness that makes it hard for children to breathe, to eat drink and exercise hard. These babies often die when they are 2 years old. Other forms of SMA are not as severe as tip 1 but still cause significant disability. Although some symptoms of SMA may be reduced, there is currently no treatment that can alter the course of the disease.

SMA caused by the mutation of the SMN1 gene. Researchers studying the genetic characteristics of SMA have discovered that there is another gene, called the SMN2 gene, on the same chromosome. While normal SMN1 genes produce functional proteins of the usual length, most of the proteins produced by the SMN2 gene are shorter and cannot function. Only a relatively small amount of normal SMN proteins produced by the SMN2 gene may also help alleviate the severity of the disease. Thus, researchers are working on drugs that increase the amount of normal protein produced by the SMN2 gene.

The new study, directed by Dr. Fischbeck's doctor Charlotte J. Sumner, NINDS, tested a drug called Trichostatin A (TSA) that belongs to a class of drugs that block histone deacetylase (HDAC). This group of drugs works to increase the activity of some genes in the body.

Previous studies have shown that HDAC inhibitors may increase the expression of SMN2 genes in transplanted cells, and the use of HDAC inhibitors to treat pregnant mice may prolong the life of Born baby mice with SMA . Initial clinical trials are underway to test HDAC inhibitors on children with SMA. However, drugs used in these clinical trials are mild HDAC inhibitors, have biological effects that may limit the useful properties of the drug in treating this disease. Most importantly, no previous study has demonstrated that HDAC inhibitors can prolong life if the drug is used after the onset of symptoms.

In the new study, the researchers tested TSA, a strong HDAC inhibitor, on cells taken from SMA patients and on SMA mice. They found that the drug helped increase the activity of the SMN2 gene in both transplanted cells as well as in mice.

Two mice with a genetic defect similar to those with motor neuron disease are called spinal muscular dystrophy.Both mice were 11 days old.The left side is treated with Trichostatin A, which increases the activity of some genes.The right child is not treated with this medicine.The treated child can stand upright and support his or her weight on the legs.And the other one is smaller due to the effects of the disease, it cannot go back to normal and doesn't support the weight of its body.(Photo: NIH)

Then, when the pups were 5 days old, when the rats showed symptoms of obvious disease such as significant weight loss and no reflexes, or unable to stand by themselves after being placed On their backs, researchers began injecting TSA every day for SMA mice. Mice treated with TSA lived on average 19% longer than untreated mice. About half of the treated mice had improved life compared to the control mice. ¼ there is no sign of improvement.

Treated mice had less weight loss and balanced reflexes, better walking and holding capacity of the front legs than untreated mice. Test results showed that mice treated with TSA also had more nerve cells in the spinal cord, thicker muscle fibers and muscle mass than did untreated mice.

Dr. Sumner said: 'This is an experiment to prove the concept. This test clearly demonstrates that this treatment can help improve the condition of the disease in mice. ' She warned that although the results of this study are attractive, there has been no research showing the efficacy of HDAC inhibitors in humans.

Dr Sumner said: The researchers are currently testing whether earlier TSA treatment in the course of the disease will work better than late treatment. They also plan to test other HDAC inhibitors in mice and correctly study how these drugs affect the course of the disease. While TSA production is very expensive and the drug has not been approved for clinical use, similar drugs developed to treat cancer and other diseases may also be useful in treating SMA.

Hong Linh