2014 SMA Researcher Meeting Summary: SMA Pathology

We will be posting a series of summaries from our 2014 researcher meeting, highlighting some of the most interesting new developments and discoveries presented there. This is the second of four total updates, and the second of two in basic research.

This summary was written by Cure SMA Scientific Advisory Board (SAB) member Samuel Pfaff, PhD. Dr. Thomas Crawford, also a member of the SAB, was the moderator for this session.

SMA Pathology I and II

In this session, nine presentations were given using animal models of SMA. Important themes from these presentations included what exactly goes wrong in SMA, what tissues are affected, what stages of development are affected, how we can accurately measure what goes wrong, and how late can be symptoms be rescued for each SMA type.

The first two talks explored which tissues influence SMA. Though SMN protein is present in every cell, SMA has the biggest effect on the motor system. Christian Lorson, a Cure SMA-funded researcher from the University of Missouri, described an innovative genetic method for testing whether astrocytes, which are support cells for neurons, contribute to SMA.

His lab increased SMN protein levels specifically in astrocytes in mouse models of SMA, while leaving SMN levels low everywhere else. They observed modest increases in life spans and improvements in motor neuron synapses, suggesting that SMN deficiency in astrocytes might contribute to SMA.

XiXi Lee, from the Cure SMA-funded Sumer Lab at Johns Hopkins School of Medicine, described an analysis of Schwann cells, which provide insulation, called myelin, around motor axons. Data shows a reduction in the number and diameter of myelinated axons in tissues from autopsies of SMA type I patients. However, increasing SMN levels in Schwann cells had no impact on motor behavior or survival in mice.

The next two talks explored the idea that some classes or subtypes of motor neurons are more vulnerable to lowered SMN levels than others. A class is a group of motor neurons that originate in the same location on the spinal cord, and go to similar areas of the body. First, Justin Lee from the Henderson lab at Columbia University described which neuron classes are affected by SMA. The group performed an analysis of motor unit vulnerability in both human SMA and mouse models.

In severe mouse models of SMA, they found 35-50 % loss in certain neuronal populations at birth, with even greater percentages later in disease progression, while other classes remained almost entirely unaffected. For example, motor neurons going to the face and controlling biting and chewing showed motor neuron loss, while the motor neurons controlling eye movement remained unaffected in mouse models of SMA.

Lyndsay Murray, a Cure SMA-funded researcher from Edinburgh University, presented data on identifying genetic differences among vulnerable and non-vulnerable motor neuron subtypes in SMA. Her work implies that there are a number of cellular pathways which are affected differently, depending on whether the motor neurons are vulnerable or resistant (non-vulnerable). A number of these pathways are candidates for further research, and possible targets for SMA drug development. Together, these two studies are beginning to uncover clues on why some motor neurons are more susceptible to SMA than others.

The next two talks focused on the role of SMN in forming motor circuits. In SMA motor neurons eventually die. But studies from animal models reveal that neuronal circuits are also disrupted, even before motor neuron death.

A neuronal circuit is a group of neurons that works together to perform a specific task. Functional motor circuits require correct development of motor neurons, sensory neurons and myelinating Schwann cells. Christine Beattie of OSU used c. elegans, a tiny worm, to explore how circuits are formed in SMA. Using the worm as a model, she concluded that abnormalities in the motor neurons themselves are the primary defect in the motor circuit, rather than defects in sensory neurons or in Schwann cells.

Anna Janas, from the Pellizzoni lab at Columbia University, discussed this same topic in mouse models of SMA. Their lab created mice with lowered SMN in selected tissues, but normal levels in everywhere else. The results showed that cell death is induced by SMN deficiency in the motor neurons themselves.

However, motor circuitry defects seem to arise from loss of SMN in cells other than motor neurons, in contrast to the findings in worms. Their data suggests that circuit disruption and motor neuron death in mice are distinct events, originating from SMN deficiency in different cell types.

The session ended with three important talks exploring new outcomes measures, also called endpoints, for drug testing in SMA mouse models. These endpoints measure disease progression in mice in ways that are relevant to human disease, increasing confidence that mouse testing is reflective of human disease.

David Arnold from OSU discussed the importance of determining the most effective timing for delivery of therapies in SMA. Motor unit number estimation (MUNE) and compound muscle action potential (CMAP) provide information about the motor neurons that control muscle movement. They are often used in clinical evaluation of SMA patients, and they can also be used to assess disease progression in SMA mouse models.

He used these techniques to assess the effects of delayed SMN restoration in a severe mouse models of SMA, with SMN protein levels restored at either 4, 6, or 8 days after birth. Median survival in mice injected at 6 days after birth (22 days) was significantly less compared to mice injected at 4 days (>60 days) after birth. There was no significant difference in survival with injection at 8 days compared to untreated mice (13 days). These results demonstrated that delayed SMN restoration can lead to some motor unit rescue but it is reduced compared to early SMN restoration.

Christine DiDonato, a Cure SMA-funded researcher from Northwestern University, next showed that mild and intermediate SMA mice exhibited muscle weakness, atrophy and motor neuron loss, confirmed by MUNE and CMAP. This suggests these mice could be useful in testing drugs targeted to SMA type II and III patients.

In addition, the MUNE and CMAP techniques will likely be utilized more frequently in the future in SMA mouse models studies, given their proven relevance to human disease, to provide new insight into the timing of motor unit dysfunction across SMA types and to test novel drug candidates. Importantly, this group of studies indicates that electrophysiological measures like MUNE and CMAP are promising endpoints in both mice and humans.

The final talk of the session was given by Seward Rutkove of Beth Israel Deaconess Medical Center/Harvard Medical School. His work assessed a novel endpoint for SMA called electrical impedance myography (EIM). EIM is a non-invasive, painless method for the assessment of muscle. It has shown sensitivity to disease status in children with SMA and is being further assessed in the NINDS NeuroNEXT biomarker study for SMA to determine whether it is appropriate for use in SMA clinical trials.

Dr. Rutkove wanted to determine whether EIM is appropriate for studies in SMA mouse models. His previous work suggested that the technique can detect subtle changes in mild SMA mouse models, but it remains unknown whether it can identify abnormalities in more severely affected mouse models.

In the current study, EIM detected an increase in the peak frequency in severe models of SMA compared to healthy mouse pups, suggesting the occurrence of muscle fiber deterioration. While preliminary, these findings indicate that EIM may serve as an effective tool for discriminating normal from abnormal muscle growth and maturation in mouse pups modeling a severe form of SMA.

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