New Treatment Delivery Method Shows Promise in Mice with SMA

Researchers have found a promising new drug delivery method for spinal muscular atrophy (SMA), a degenerative disease that affects the motor nerve cells in the spinal cord of children. Although there is a treatment for this disease, the lack of an effective delivery system is an obstacle for its widespread use. This new treatment method, tested in mice, was shown to be simpler, safer, and effective.

The study, “Systemic Peptide-Mediated Oligonucleotide Therapy Improves Long-Term Survival In Spinal Muscular Atrophy,” was published in the journal Proceedings of the National Academy of Sciences. 

Children develop SMA when mutations in the SM1 gene block the production of the SMN protein. This protein is necessary for the proper development and functioning of the spine, and its absence triggers the death of motor neurons and muscle weakness.

The proposed therapies for SMA have included the delivery of a modified version of SMN2, encoded by a gene similar to SMN1, to promote the production of enough SMN protein. This therapy is called splice-switching oligonucleotide (SSO).

However, it’s not possible to deliver SSOs to the brain and into the central nervous system because they do not cross the blood-brain barrier, which protects the brain by selecting which molecules cross it and which don’t. The only way to do this is to directly inject SSOs into the spine with a lumbar puncture. But this isn’t the most optimal method for several reasons.

“Intrathecal delivery — injection around the spinal cord — makes a treatment less straightforward,” researcher Suzan Hammond, who conducted the study at England’s University of Oxford, said in a news release. “Around a third of patients experience side effects. An additional complication is that SMA frequently leads to scoliosis — twisting of the spine — which can restrict such injections.”

To overcome these issues, the team developed a new delivery system for SSOs called Pip6a-PMO, in which a protein called Pip6a helps deliver SSOs to the central nervous system. To test the procedure, the team injected Pip6a-PMO in young mice with SMA. At seven days old, the mice already presented signs of improvement, such as weighing more and growing faster compared to those who did not receive the treatment.

A single dose of Pip6a-PMO extended life from 12 to 167 days (fourteen times longer than observed in untreated mice), and a second dose increased life to 457 days (38 times longer than the untreated animals). SMA causes the destruction of the communication points between motor neurons and muscle cells, but a single dose of Pip6a-PMO was able to recover these connections.

“While Pip6a was initially designed for Duchenne muscular dystrophy, we have shown that it can also be highly effective in SMA treatment,” said Matthew Wood, the leading author of the study. “The survival of mice in this trial was far longer than any other treatment. The advantage is that it is both a central nervous system treatment and a systemic treatment for the wider body.”

The researchers believe this delivery method can also work for patients of other diseases, such as Parkinson’s, Huntington’s and ALS, and are developing a clinical trial they hope to initiate next year to investigate the clinical application of Pip6a-PMO in human patients.