Researchers discovered that the administration of SMN therapeutics can potentially enhance neuromuscular junction recovery in patients with spinal muscular atrophy (SMA), and published their results in Human Molecular Genetics.
One of the key characteristics of SMA is the loss of motor neurons and neuromuscular junctions. Currently, approved therapies for SMA have been shown to slow disease progression due to their ability to replenish missing SMN protein. However, studies demonstrate that there is only a short therapeutic time window before irreversible damage occurs.
In addition, scientists do not have data on the long-term effects of SMA therapeutics. “It is likely that long term outcomes will be closely linked to the amount of damage at the point of treatment and the degree to which motor neuron pathology can be reversed,” Comley and colleagues wrote.
Read more about SMA etiology
Early data concerning the use of SMN therapeutics to treat SMA suggest that they can reduce neuromuscular junction defects. This is contingent on the route of administration and the levels of SMN achieved through therapy. However, a key ambiguity is whether SMN therapy merely prevents the manifestation of defects or whether it genuinely corrects SMA-associated pathology.
The authors of this study conducted a clinical trial using an SMA mouse model. These model mice were at the P4 stage, demonstrating high SMA-associated pathologies, such as presynaptic swelling, denervation, and a rise in transcripts associated with the P53 pathway. Following SMN therapy, the research team reported “a remarkable recovery of the neuromuscular system within 6 days, suggesting that much of the pathology observed at P4 is rapidly reversible.”
This study highlights the massive regenerative capacity of both motor neurons and neuromuscular junctions following SMN restoration. Future studies should be focused on investigating whether similar outcomes can be achieved in human patients and the long-term impact of SMN therapy.
Comley LH, Kline RA, Thomson AK, et al. Motor unit recovery following Smn restoration in mouse models of spinal muscular atrophy. Hum Mol Genet. Published online May 12, 2022. doi:10.1093/hmg/ddac097