Recent Advances in Treatment of Spinal Muscular Atrophy (2017)
Spinal Muscular Atrophy (SMA) is a disease affecting the motor neurons i.e. nerve cells controlling the contraction and movement of muscles, that causes severe generalized weakness and wasting. The disease occurs in different forms, depending on the age of onset and severity. The most severe form SMA type I or Werdig-Hoffman disease begins in infancy, the intermediate form SMA type II presents in early to late childhood, while the mildest form SMA type III or Kugelberg-Welander disease presents in adolescence or young adulthood.
SMA is caused by mutations (or defects) in a gene called the survival motor neuron 1 (SMN1) gene, resulting in absence of SMN1 protein. However, the genetic nature of the disease is more complicated because near to the SMN1 gene is another gene that is almost, but not exactly, the same called SMN2. The SMN2 gene produces a protein that can partially compensate for absence of SMN1 protein but this compensation is very limited. Some people have more than one SMN2 gene. In SMN patients, it has been shown that the more copies of SMN2 gene they have, the milder the disease. Indeed, it appears that five copies of SMN2 genes may be sufficient to compensate for absence of SMN1 protein in SMA. This immediately suggested to scientists were able to treat SMA by making the SMN2 gene produce more protein than usual.
In a mouse model of SMA, scientists were able to show that a compound called sodium butyrate could upregulate the SMN2 gene to produce more SMN2 protein, and in this way, reduce the severity of the disease. Subsequently, clinical trials to test the effect of compounds that may upregulate the SMN2 gene were begun in children with SMA. There are now several such trials ongoing. One is a trial in children with SMA using valproic acid, because valproic acid has some chemical actions similar to sodium butyrate. Another ongoing clinical trial involves a compound called sodium phenylbutyrate, which is related to sodium butyrate, but may be less toxic. In addition, there are two other on-going studies using hydroxyurea in the different types of SMA patients. Hydroxyurea has also been shown in experiment to upregulate SMN2 gene in cells. These trials bring hope to patients with SMA and their families, and their results are eagerly awaited.
By Dr Ong Hian Tat