Affecting nearly 1 in every 6000 births, spinal muscular atrophy (SMA) is one of the most common genetic muscle-wasting disorders among people around the world. SMA is an autosomal recessive disorder meaning two copies of the mutated gene are needed for any symptoms to occur. These symptoms occur from the survival motor neuron 1 gene (SMN1) being mutated and effecting the production levels of survival motor neuron proteins (SMNP). SMNPs are pivotal for the development of motor neurons in our body and when there are lower levels being produced at the improper time, muscles under-develop. Researchers at Johns Hopkins University have found a possible solution to help relieve symptoms of SMA by targeting a long non-coding RNA (lncRNA).
As the researchers were trying to discover a reason why different levels of SMNPs were being produced, they came across a survival motor neuron gene (SMN) that encoded a lncRNA that was expressed during early muscle development. During normal early development, the SMN lncRNA was expressed at low levels to allow for regular production of SMNPs. In later development, the SMN lncRNA is expressed more which reduces the production of SMNPs. With SMA, the pattern is reversed which leads to muscle-wasting or even death. In theory then, if SMN lncRNA was somehow regulated and the expression pattern reversed, some of the symptoms of SMA would be relieved. In fact, that’s exactly what the researchers set out to do with a tag team of compounds including one of the newest drugs on the market.
The first drug Spinraza (Nusinersen), is a newly FDA-approved drug that is currently the only drug on the market for SMA. The drug is an antisense oligonucleotide which is a strand of DNA or RNA that is complementary to another known sequence. What is special about Spinraza is that it induces splicing where it binds to the known sequence. Spinraza binds to the highly similar SMN1 gene called SMN2 and cuts it at a specific location. The cut that is made converts the SMN2 gene into a SMN1 gene that if fully functional. The second compound used was also an antisense oligonucleotide-A (ASO-A) that interacts with the SMN lncRNA. ASO-A binds to the lncRNA and reduces its expression which up-regulates SMNP production.
Having Spinraza create a functional SMN1 gene and ASO-A block SMN lncRNA from down-regulating SMNP production is a great one-two punch. To prove this, mice models were tested upon and mice who were treated with both compounds lived longer and gained muscle mass when compared to mice who were treated solely with Spinraza or other compounds.
Even though this dynamic duo of drugs does not cure SMA all together, it is a start to understanding the disorder and what role lncRNA plays. Hopefully, further research and development can be done to not only to better the drugs but also to reduce the cost of Spinraza which currently stands at a hefty price tag of $750,000 per year.
For further information, feel free to check out the article below:
New York Times article on the cost of Spinraza:
