Central and Peripheral Treatment of SMA meeting summary

On November 10th, the SMA Foundation held a meeting with over 100 SMA researchers, clinicians, and patient advocacy group representatives to discuss the potential impact of SMN upregulation outside of the central nervous system (CNS). The meeting focused on evidence from preclinical models and patients that indicate SMN has a role outside of the CNS and the implications of these data for systemic treatment of SMA.

The session started with an overview from Dr. Karen Chen. Dr. Chen noted that while it is widely accepted that SMN protein is essential for the CNS and muscle, there is increasing evidence that SMN could also play an important role outside of these tissues. The question of whether the phenotypes observed in SMA outside of the CNS are secondary to motor neuron loss, the result of immobility, or the direct result of SMN loss in these tissues organs will be discussed in this session.

Dr. Basil Darras from Boston Children’s Hospital presented an overview of the clinical data that indicate that SMN protein deficiency compromises the function of other tissues outside of the CNS. Dr. Darras highlighted examples from multiple published studies that demonstrate multiple tissues are affected in SMA patients including muscle, vasculature, liver, pancreas, and gastrointestinal tract. Given the number of phenotypes observed in peripheral tissues, Dr. Darras concluded that thinking of SMA as a disease solely of motor neurons is an oversimplification.

SMA researchers then presented results from preclinical models that suggest SMA is a whole-body disease. Dr. Tom Gillingwater from the University of Edinburgh began by presenting data from Dr. Adrian Krainer’s lab that showed SMN restoration in the peripheral tissues is critical for long-term survival in SMA mice, demonstrating the importance of SMN outside of the CNS. For the rest of his talk, Dr. Gillingwater focused on nonneuronal cells and tissues that are affected in SMA models and patients.  Dr. Gillingwater described work from his own lab and others that show neuromuscular junctions (NMJs) are disrupted in both SMA mouse models and patients and that these defects occur before the loss of motor neurons. He went on to show that motor neurons in both SMA mouse models and patients have defects in myelination. These defects can be rescued in mouse models by restoring SMN levels in Schwann cells, demonstrating a Schwann cell-intrinsic role in SMA pathology. Dr. Gillingwater next focused on vascularization defects observed in SMA. Work from his lab shows a vascular depletion in the muscle of both SMA mouse models and patients. SMA mouse models also had decreased vascularization in the spinal cord, resulting hypoxia of motor neurons and possibly contributing to SMA pathogenesis.

SMA researcher Dr. Rashmi Kothary from Ottawa Hospital Research Institute spoke next about musculoskeletal defects in SMA. Dr. Kothary began by providing an overview of studies that focus on the role of SMN in muscle development and maintenance. He presented results from both SMA mouse models and patients that demonstrated SMN depletion results in muscle-intrinsic defects such as reduced satellite cell number, a delay in the myogenic program, reduced myoblast fusion, and molecular homeostasis disruption. Dr. Kothary also presented his own lab’s unpublished data from a novel mild mouse model of SMA. Results from this model show evidence of myopathy and muscle weakness in the absence of neuron loss, which further indicate the intrinsic role of SMN in the muscle. Dr. Kothary then presented work from other labs on how bone is affected in SMA. He showed evidence of decreased bone volume in SMA mouse models of various severity, as well as increased fractures and osteoclast formation. Importantly, reduced bone density and a high prevalence of fractures have also been reported in SMA patients. Dr. Kothary concluded his presentation by stressing the need of SMN upregulation in tissues outside of the CNS.

Dr. Lee Rubin from Harvard University finished the preclinical session by describing work from his lab using induced pluripotent stem cells (iPSCs) from SMA patients and SMA mouse models. Dr. Rubin showed that iPSCs from SMA patients exhibit skewed proliferation and differentiation compared to unaffected individuals. Consistent with these findings, satellite cells from SMA mice differentiate prematurely both in vivo and in vitro and form fewer myotubes. Dr. Rubin further showed that a depletion of SMN in satellite cells prevents regeneration after the muscle has been damaged. These results further support that SMN plays an important role in muscle development. For the last part of his presentation, Dr. Rubin used records from an electronic medical database to address whether SMA patients exhibit other systemic symptoms before their SMA diagnosis. His lab’s preliminary results suggest an increased prevalence of a variety phenotypes outside of the CNS in Type III patients compared to an age-matched non-SMA population. Dr. Rubin concluded that these results point to a likelihood of significant systemic defects in SMA patients that are potentially independent of motor neuron loss.

Ying Qian next moderated a discussion with members of the SMA Foundation Patient Advisory Board and representatives from several SMA patient advocacy groups in order to hear patients’ perspective on SMA as a whole body disease. The most common symptoms participants spoke of were fatigue and sensitivity to cold. Some representatives also reported symptoms such as gastrointestinal issues (constipation and diarrhea), kidney stones, wound healing issues, edema and osteoporosis. SMA Foundation Patient Advisory Board member Amelie Gubitz finished the discussion by suggesting these issues be followed in natural history studies.*

Dr. Chen ended the session by moderating an open discussion with all meeting participants. Some clinicians raised the possibility that the phenotypes described by presenters could be secondary to motor neuron loss or due to immobility and thought additional data and biomarker studies would provide more insight. However, many clinicians spoke of their own observations of peripheral symptoms in SMA patients such as gastrointestinal issues and metabolic defects that are not as common in other neuromuscular diseases, suggesting a direct role of SMN in peripheral tissues. It was also suggested that more manifestations outside of the nervous system may be observed as severe Type I patients survive longer with SMN upregulation in the CNS only.  Overall, participants agreed that systemic SMN upregulation could provide more benefit to SMA patients.

* For more information regarding comments provided by patient advocacy group representatives, please contact Ying Qian ([email protected]).


Dr. Basil Darras

Dr. Thomas Gillingwater

Dr. Rashmi Kothary

Dr. Lee Rubin