The SMA Researcher Meeting is the largest research meeting in the world specifically focused on SMA. This year we had a record setting 350 attendees. The goal of the meeting is to create open communication of early, unpublished scientific data, accelerating the pace of research. The meeting also furthers research by building productive collaborations—including cross-disciplinary dialogue, partnerships, integration of new researchers and drug companies, and educational opportunities for junior researchers.

We will be posting a series of summaries from our 2016 researcher meeting, highlighting some of the most interesting new developments and discoveries presented there. This update covers the second of two sessions on therapeutic targets. Research has revealed that a number of systems, pathways and processes are affected in SMA. The presenters in these two sessions are investigating these different aspects of SMA, looking for new ways to treat SMA that target other areas. Ultimately, these approaches could be used in combination with approaches that address the underlying genetics of SMA, giving us the best chance of a comprehensive, effective treatment. This is particularly important as we seek to develop treatments for all ages, stages and types of SMA.

This session was moderated by Cure SMA Scientific Advisory Board Member Umrao Monani, PhD.

The session began with a presentation by Mehdi Eshraghi, PhD candidate (University of Ottawa), who described how different genetic backgrounds alter disease severity in SMA model mice. SMA mice created on a commonly used white strain (FVB/N) of mice were found to be more severely affected than those on a related black strain (C57Bl/6), suggesting genetic differences, outside the SMN gene region, that govern how SMA evolves during the course of the disease. This is a critical first step in identifying molecules that mediate the effects of the SMN protein.

The next speaker, Amanda Guise, PhD (Harvard Medical School), discussed her attempts to identify the group of proteins, in spinal cord tissue, that are altered in SMA. Using a technique called mass spectrometry, which allows one to monitor levels of thousands of proteins in a diseased organ, she showed that the process (translation) involved in turning information coded in ribonucleic acid (RNA) into proteins is greatly disrupted in SMA. Further examination of such changes could hold the key to understanding neuromuscular dysfunction in SMA.

The third presentation was made by Dr. Melissa Bowerman, PhD (Oxford University), who focused on a molecular pathway featuring glucocorticoids (steroid hormones) and the KLF15 protein. Her results suggest that KLF15, which is a key regulator of glucose, amino acids (the building blocks of proteins) and lipids, is at abnormally low levels in muscle from SMA model mice. Since KLF15 is itself regulated by glucocorticoids, Dr. Bowerman and her colleagues also examined levels of the latter, finding them to be at low levels too. One implication of the study is that this pathway, which appears to be perturbed in human SMA patients as well, might be modulated as an adjunct therapy for secondary aspects of the disease.

One caveat of some of the most commonly used SMA model mice is their extreme severity. Since SMA patients exhibit a spectrum of disease severities, such model mice might not accurately represent intermediate or mild SMA. Accordingly, the penultimate speaker, Kevin Kaifer, a graduate student in Dr. Chris Lorson’s lab (University of Missouri), described his efforts to generate a milder mouse model of SMA. This was accomplished by administering the severe mice with sub-optimal doses of SMN-enhancing agents. The utility of the “new” mild SMA mice was then demonstrated by gauging the effects of putative modifiers of the disease. One such modifier,Plastin3, an actin-binding protein, which does not modify the disease in severe SMA mice, did have a mitigating effect on the mildly affected model mouse. If this is generally true, the new mice could serve as useful tools in better understanding SMA biology.

The final speaker of the session, Dr. Brunhilde Wirth, PhD (University of Cologne), highlighted work demonstrating the relevance of endocytosis, a form of active transport whereby the cell transports molecules by engulfing them, in SMA. Work from her lab has shown that two actin-binding proteins which may modifySMA disease, Plastin3 and Coronin1C, impact endocytosis. Modulating these two proteins alters disease state in SMA animal models. Dr. Wirth’s work identifies a new and potentially exciting point of intervention in the treatment of SMA. Altering levels of molecules involved in endocytosis might be used in conjunction with SMN-enhancing agents in a combination therapy of the future.