The annual SMA Researcher Meeting is the largest research meeting in the world specifically focused on SMA. This year, we had a record setting 735 attendees join together in Anaheim, CA. The goal of the meeting is to create open communication of early, unpublished data, accelerating the pace of research.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.

This is the second in a series of summaries from our 2019 researcher meeting, highlighting the most interesting new discoveries presented there. This update covers the basic research sessions held at the conference that focused on modifiers of disease and therapeutic targets, SMN function and expression, and splicing, and SMA pathology and tissue requirements.

Basic Research Session 1: Identification of Candidate Therapeutic Targets and Disease Modifiers

The first session, Identification of Candidate Therapeutic Targets and Disease Modifiers was moderated by Dr. Umrao Monani (Columbia University). It began with a plenary talk by Dr. Paul Taylor of St. Jude’s Hospital, Memphis.  While Dr. Taylor’s presentation did not focus per se on SMA, it did expand on novel mechanisms in an allied disease, amyotrophic lateral sclerosis.  Specifically, Dr. Taylor spoke of interesting work his lab has carried out demonstrating the role of “low complexity DNA domains” in triggering the separation of various disease-related macromolecules into different liquid phases and the consequence of such a process in neurodegeneration.  Dr. Taylor’s talk was followed by Dr. Kevin Kaifer (University of Missouri).  Dr. Kaifer spoke about a micro-RNA (miR-23a) and its role as a protective modifier of disease in SMA mouse models. The third presentation of the session was made by Dr. Brunhilde Wirth (University of Cologne, Germany) who elaborated on an SMA modifier, NCALD, which her lab previously identified.  Dr. Wirth’s research responded to concerns that reducing the expression of NCALD (which ameliorates SMA in model mice) might nevertheless be deleterious in other respects.  She showed that while a complete loss of NCALD expression causes brain pathology, loss of only one copy of the gene is less toxic and may be used to mitigate SMA severity.

The fourth presentation during this session was from Dr. Yongcaho Ma (Northwestern University) Dr. Ma provided evidence that mitochondria, the powerhouses of the cell, are unhealthy in SMA model mice.  It was therefore suggested that improving mitochondrial function might be a means of treating SMA.  Dr. Darija Soltic (Keele University) presented next, describing the results of experiments that showed dysfunction of the lamin A protein in SMA.  It was proposed that dysfunction of lamin A is especially harmful to the heart in animal models. Akin to dysfunction in lamin A in SMA, Dr. Laxman Gangwani (Texas Tech University) spoke of defects in the Senataxin protein in SMA cells from humans and model mice.  Deficiency of which can lead to accumulation of DNA damage in SMA. Dr. Gangwani’s work suggests that the way Senataxin repairs breaks in DNA leaves neurons especially vulnerable to loss of the protein and that therefore, Senataxin may be another potential suppressor of SMA.  The next speaker, Dr. Joe Hoolachan (Keele University) spoke of work that focused on identifying muscle-specific targets in SMA.  Dr. Hoolachan’s work identified the Bco1 protein as a potential target to treat the muscle in SMA. The following speaker, Min-Jeong Kye (University of Cologne, Germany) also examined the role of muscle in SMA and showed that the CTRP3 protein may be an important factor that regulates motor neuron health.  CTRP3 levels are reduced in SMA muscle and were shown to negatively affect the ability of motor neurons to extend axons. Next, Dr. Monica Nizzardo (University of Milan) provided results of pre-clinical research in which SMN-enhancing oligonucleotides such as Spinraza could be linked to cell-penetrating peptides to enhance the efficiency with which the oligonucleotides target cells.  A series of peptides were tested, and the most efficient ones identified for future studies.  In the final talk candidate therapeutic targets and disease modifiers session, Dr. Christiano Alves (Massachusetts General) presented data examining the feasibility of using the L1000 gene expression system to rapidly analyze genes whose expression in blood from SMA patients changes following treatment with drugs such as Spinraza.  The system was found to be both simple and cost-effective and was used to detect changes in actin cytoskeleton genes in blood from SMA patients.

Basic Research Session 2: SMN Function, Expression and Splicing

The second session, SMN Function, Expression and Splicing, was moderated by Dr. Adrian Krainer (Cold Spring Harbor Laboratory). The session began with a plenary talk by Dr. Charlotte Sumner (Johns Hopkins University School of Medicine) addressing the need for normal SMN protein levels as a function of time during prenatal development and postnatally. This was followed by a talk from Daniel Ramos (Johns Hopkins University School of Medicine), a student in Dr. Sumner’s lab. Structural defects were revealed to be present prenatally, by analysis of fetal SMA spinal cords and nerve roots. SMN protein levels normally go down postnatally, and they are further reduced in SMA-patient tissues. Furthermore, they are beginning to look at SMN protein levels and SMN2 splicing in patients who had received Nusinersen.

In the next talk, Dr. Utz Fischer (University of Würzburg, Germany) described a screen for regulatory protein kinases that interact with components of the SMN complex. Small-molecule drugs that target these kinases could find uses in the context of SMA therapy. Dr. Alberto Kornblihtt (Universidad de Buenos Aires, Argentina) addressed the role of chromatin structure in modulating the splicing of SMN2. He showed that a more open chromatin results in faster transcriptional elongation facilitating exon 7 inclusion of SMN2. Paradoxically, an antisense oligonucleotide (ASO) that promotes exon 7 inclusion resulted in a more compact chromatin resulting in less exon 7 inclusion, though its net effect is still increased exon 7 inclusion, because of its direct action on splicing. Combining chromatin-decondensing HDAC inhibitors, such as TSA or VPA, with the ASO, resulted in higher exon 7 inclusion than with the ASO alone, both in cultured cells and in SMA mouse models.

In the final talk of the SMN Function, Expression, and Splicing session, Dr. Sarah Tisdale (Columbia University) described the role of U7 snRNP, an RNA molecule, in maintaining the integrity of the neuromuscular junction. Assembly of U7 snRNP is compromised when SMN levels are below normal. She described a way to restore U7 levels independently of SMN observing improvements in NMJ integrity and motor function in SMA mice.

Basic Research Session 3: SMA Pathology and Tissue Requirements

The final basic research session, SMA Pathology and Tissue Requirements was moderated by Dr. Christine DiDonato (Northwestern University) and consisted of two talks. The first of which was given by Dr. Jeong-Ki Kim (Columbia University). Dr. Kim described his use of a mouse model in which SMN can be selectively reduced in skeletal muscle. Using this model, he demonstrated that loss of SMN only in muscle triggered sever phenotypes in mice with one copy of SMN2. Furthermore, restoring SMN protein levels following the onset of muscle pathology reveres disease phenotypes indicating a role of muscle in SMA. The final talk by Lingling Kong (Johns Hopkins University) described her work investigating serum neurofilament light chain (NF-L) as a biomarker of early postnatal degeneration of immature SMN motor axons. Using both human autopsy tissue and an SMA mouse model, she demonstrated that defects in SMA motor axons begin embryonically and that these immature axons subsequently rapidly degenerate in the neonatal period, leading to elevated NF-L levels in blood. These results indicate that blood NF-L levels by may be a sensitive marker of early degenerative events in severe SMA infants.