Harvard Team Finds Compound to Restore Protein That Is Short in SMA

Researchers at the Harvard Stem Cell Institute have identified a compound that can restore the SMN motor-neuron protein whose shortage is associated with spinal muscular atrophy (SMA).

“This discovery opens up new lines of drug interrogation,” Lee Rubin, the senior author of the study, said in a news story written by Harvard’s Hannah L. Robbins.

The team’s research, “Single-Cell Analysis of SMN Reveals Its Broader Role in Neuromuscular Disease,” was published in Cell Reports.

SMA is characterized mutations or deletion of the gene that encodes the survival of the SMN protein. Because of this, many motor neurons in SMA patients are unable to produce the necessary amounts of SMN, causing cellular stress and even cell death. This problem in SMN deregulation is what ultimately generates the motor and muscular symptoms in SMA.

Instead of trying to correct the defective gene, the researchers found a way to stabilize the SMN protein to keep its concentration at the levels needed for a normal cellular response.

The team discovered that motor neurons affected by the disease were not dying at the same time, although all carried the same mutation. This observation could be explained by levels of SMN in the neurons, the researchers said.

Motor neurons with higher SMN levels were likely to survive longer than those with lower levels, they learned. This was true not only in motor neurons affected by SMA but also in normal motor neurons and those affected by amyotrophic lateral sclerosis (ALS).

“It is clear that the SMN protein is necessary for all motor neuron survival, not just motor neurons targeted by ALS or SMA,” said Natalia Rodríguez-Muela, co-first author of the study.

These observations suggested that if the team could find a way to increase the amount of the SMN protein, the motor neurons might be protected from early death.

They tested a compound that could inhibit the process responsible for SMN normal degradation. It increased the level of SMN protein in motor neurons, they found. As a consequence, the compound promoted the survival of human motor neuron cells in a laboratory.

The compound also improved symptoms in animal models of SMA, even in more severe forms of the disease.

“This process points to an unexplored therapeutic direction that could benefit patients of not one, but two, separate diseases,” Rubin said.

Harvard’s Office of Technology Development has filed a patent application on the new therapeutic approach.