The Annual SMA Researcher Meeting is the largest research meeting in the world specifically focused on SMA. This year we had a record setting 470 attendees. The goal of the meeting is to create open communication of early, unpublished data, accelerating the pace of research. The meeting also furthers research by building collaborations—including cross-disciplinary dialogue, partnerships, integration of new researchers and drug companies, and educational opportunities for junior researchers.
We are posting a series of summaries from our 2017 researcher meeting, highlighting the most interesting new discoveries that were presented. This update covers the session, “Regulation of Splicing and SMN Protein Expression”, moderated by Dr. Arthur Burghes, PhD, a member of the Cure SMA scientific advisory board.
To begin the session, Friedrich Metzger, Roche Pharmaceuticals, described several potent and specific molecules that are able to correct the SMN2 splicing defect with a high degree of specificity, meaning that they only target the SMN2 gene. These molecules are now in the early stages of therapy development. Next, Antoine Cléry from the Swiss Federal Institute of Technology (ETH) in Zurich, spoke about his team’s work to change the specificity or affinity of splicing regulators for their targets using changes in the target protein sequence or small molecules. This work describes a new strategy which could be used to modulate regulators of SMN2 splicing in order to generate more SMN protein.
The next talk by John Staropoli, Biogen, investigated how disruption of the functions of SMN leads to neurodegeneration. He provided data showing that the SMN deficiency, as is the case in SMA, causes pervasive splicing defects and triggers a global DNA damage and stress response. This DNA damage is believed to lead to motor neuron death. Yimin Hua, Soochow University (China), described a novel mechanism that accounts for the discordance in disease severity seen in some SMA siblings with the same SMN2 copy number. He and his team have identified a part of the DNA sequence of SMN2 that differs in these siblings and seems to account for a milder clinical severity.
The last two speakers focused on activity of SMN protein. Utz Fischer, University of Wuerzburg (Germany), discussed the signaling and regulatory cues which he and his team have found to determine the activity of the SMN complex. Understanding how the SMN complex is regulated is important for the design of therapeutics to modulate its functions. In the final talk of the session, Francesco Lotti, Columbia University (New York), described a modification of the SMN protein that occurs after the protein is made, called sumoylation. This modification is important for proper assembly and function of the SMN complex.