2017 Researcher Meeting Summary: Identification of Candidate Therapeutic Targets and Disease Modifiers

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 The goal of the meeting is to create open communication of early, unpublished data, accelerating the pace of research.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 presented there. This update covers the session entitled, “Identification of Candidate Therapeutic Targets and Disease Modifiers”. This session consisted of two parts and was moderated by Drs. Samuel Pfaff, PhD, and Adrian Krainer, PhD, both members of the Cure SMA scientific advisory board.

To begin the session, Stefania Corti, University of Milan, described findings identifying certain RNA pathways that may be disrupted in SMA. These pathways represent potential new non-SMN therapeutic targets. Next, Yong-Chao Ma from Northwestern University and Lurie Children’s Hospital, Chicago, spoke about his team’s work to understand the mechanisms behind the defects in mitochondria, the organelle in each cell responsible for generating energy rich molecules, in SMA. He described how stopping aberrant Cdk5, a cellular protein, activation can help to reduce mitochondrial defects in addition to motor neuron degeneration. The next talk by Meaghan Van Alstyne, Columbia University, investigated the mechanisms through which SMA motor neurons degenerate. Her team found that p53, a ubiquitous cellular protein, is a major driver of motor neuron death in SMA. By performing a linkage analysis in a four generation SMN family, Brunhilde Wirth, University of Cologne, Germany, identified neurocalcin delta (NCALD) as a novel SMA disease modifying gene. She and her team found that reduced NCALD expression was able to protect individuals in this family who might have otherwise developed SMA type 3. A combinatorial approach of elevating SMN levels and decreasing NCALD might bring additional benefit to SMA patients.

The next two talks focused on dysregulation of bodily processes and systems. First, Melissa Bowerman, University of Oxford, described findings of a general perturbation of circadian rhythm in metabolic tissues of SMA mice. It is believed that this perturbation is responsible for metabolic and sleep disturbances observed in SMA mice and patients. Furthermore, the group demonstrated that SMN protein displays a circadian rhythmicity in a tissue and age dependent manner. Next, Marc-Olivier Deguise, University of Ottawa, Ontario, provided evidence that immune cells are particularly vulnerable to reduced SMN levels. Further work will be conducted to determine the defects in these cells and their contribution to neuroinflammation in SMA.

The final talks of the session involved animal models of SMA. Ashlyn Spring, University of North Carolina, described her work demonstrating that mutations in the SMN1 gene causing SMA in human patients can be modeled in fruit flies, with flies displaying many of the same physical manifestations of SMA as human patients. These models are well positioned to now be used to study the cellular and molecular mechanisms underlying SMA disease. In the final talk of the session, Mendell Rimer, Texas A&M University, described testing for nerve sprouting, a process critical for muscle fiber reinnervation following nerve injury, in a SMA mouse model treated with an SMN enhancing compound. He demonstrated that mice with increased SMN levels following treatment had more nerve sprouts than untreated animals, indicating the SMN may be able to promote sprouting.

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.

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