Proof-of-Concept Study May Have Found New Way of Treating SMA

Researchers may have discovered a new treatment for spinal muscular atrophy (SMA). Identifying a molecule that prevents the SMN2 gene from being read by protein-making machinery, they then showed that getting rid of it increased SMN protein levels.

Importantly, the approach also enhanced the effectiveness of a splice-modification drug that works much like the recently approved SMA treatment, Spinraza (nusinersen).

The researchers specifically discovered that removing a molecule called SMN-AS1 — a long non-coding RNA — increased the transcription of the SMN2 gene, making more SMN protein available. Their proof-of-concept study, “The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy,” was published in the journal Neuron.

Long non-coding RNAs (lncRNAs) are molecules that correspond to a strand of DNA. But unlike mRNA molecules that work as intermediaries between a gene and its corresponding protein, lncRNAs work to control whether a gene is active or not.

Researchers from Johns Hopkins University School of Medicine and Harvard University found that the molecule SMN-AS1 works together with another factor to prevent the SMN gene from being transcribed — that is, it prevents the mRNA from forming.

SMN-AS1 turned out to be particularly common in neurons in both the brain and spinal cord, and when the research team degraded the factor, both mRNA levels of full-length SMN2 increased. This, in turn, led to an upswing in the production of the SMN protein.

They repeated the experiments in cells gathered from SMA patients, lab-grown neurons, and in a mouse model of SMA, getting similar results in each.

In people, SMA is caused by mutations in the SMN gene, but the severity of the condition is determined by the amount of SMN protein produced from the SMN2 gene.

This second gene gives rise to mRNA that lacks a stretch, with only a small amount of normal protein being produced. But the gene can come in several copies, and patients with many SMN2 copies fare better, since they manage to produce more functioning SMN protein.

Splice-modification drugs allow more full-length SMN to be formed by changing how a pre-mRNA molecule is cut and glued together, to include the part normally missing.

Since splice-modificators work to increase the amount of protein produced, but in a different fashion from compounds that degrade SMN-AS1, researchers combined the two approaches in mice with severe SMA. They found, as they expected they might, that the SMN protein in the central nervous system increased even more with the combined treatments.

Mice receiving the combination moved better — in some tests, they performed nearly as well as healthy mice — and also survived longer than mice receiving either treatment alone.

Spinraza is an antisense oligonucleotide designed to alter the splicing of SMN2 to increase production of fully functional SMN protein. It was approved by the FDA to treat SMA in both children and adults in December 2016.