SMA Researchers and Clinicians from Around the World Gather at the 28th Annual SMA Research & Clinical Care Meeting

Podium Presentation 1. Role of DLC1 Isoform 1 in Spinal Muscular Atrophy Pathogenesis and Treatment

Martin Cheung, PhD ~ The University of Hong Kong, China

Main Points:

• The survival motor neuron (SMN) protein is critical for motor neuron health and function. Deletion of the SMN1 gene causes SMN protein deficiency in people with SMA.
• In this study, Dr. Cheung and his colleagues found that like SMN, a protein called “DLC-i1” is required for motor neuron health and function. The group discovered that DLC-i1 levels are lower in cultured human-derived and mouse cells affected by SMA, and that restoring DLC-1i levels in these SMA-affected cells improved cell health and function
• Insight into the roles of proteins like DLC-i1 in healthy and SMA-affected motor neurons may increase the number of potential targets for future SMA therapeutics.

Podium Presentation 2. Munc13-1 Local Translation Mitigates Presynaptic Pathology and Rescues Motor Function in Spinal Muscular Atrophy

Mehri Moradi, PhD ~ University Hospital of Wuerzburg, Germany

Main Points:

• SMN protein deficiency in people with SMA leads to disrupted communication between motor neurons and muscle cells at the neuromuscular synapse.
• Moradi’s group used an SMA mouse model to show that SMN protein deficiency disrupts the expression of another protein, Munc13-1, which is known to be important in relaying messages across the neuromuscular synapse.
• Understanding how SMN protein deficiency affects other proteins that are important for motor neuron health and function may reveal novel approaches to developing SMA treatments.

Podium Presentation 3. SMN Association with Alpha-COP Is Not Critical to SMA Pathogenesis

Kaitlyn Kray, MS  ~ The Ohio State University, United States

Main Points:

• SMN protein deficiency causes motor neuron loss in people with SMA. However, exactly how this occurs remains unclear.
• Kray and her colleagues used an SMA mouse model to investigate whether the interaction that has been observed between the SMN protein and another protein, alpha-COP, is necessary for motor neuron health and function. The study results indicated that binding to alpha-COP is not one of the SMN protein’s essential functions, and that disruption of this binding in SMA and is unlikely to contribute to motor neuron loss.
• Knowing which interactions between the SMN protein and other proteins are important for motor neuron health and function may inform future SMA drug development.

Podium Presentation 4. Sm-protein Rings Are Assembled on mRNAs and These mRNAs Are

Less Abundant in SMA Mice

Anton Blatnik, PhD ~ The Ohio State University, United States

Main Points:

• The SMN protein has many functions within cells, one of which is to assist in the assembly of structures known as “sm-protein rings.” Sm-protein rings are involved in processing RNA in the nucleus.
• Blatnik and his group used informatics and biochemistry techniques to identify which types of RNA molecules are able to bind to sm-protein rings. The group discovered that many of the RNA molecules that bind to sm-protein rings are a type known as “messenger RNA (mRNA).” Dr. Blatnik’s lab also found that unlike those in healthy cells, the majority of mRNA molecules in motor neurons from SMA mice cannot bind to sm-protein rings.
• These findings suggest that SMN protein deficiency may cause motor neuron loss in SMA in part by disrupting the processing of mRNA by sm-protein rings.

 

Podium Presentation 5. SMN Proteome Identify Uncharted RNA Metabolism Pathways

Olivier Binda, PhD ~ University of Ottawa, Ontario, Canada

Main Points:

• The SMN protein performs many different functions in motor neurons. Many of these functions have not yet been characterized.
• Binda’s group has previously shown that the SMN protein interacts with several other proteins called “RNA metabolism factors” that are involved in processing RNA. In this study, Dr. Binda and his colleagues used biochemistry techniques to determine that these RNA metabolism factors each bind to one of two specific regions on the SMN protein. They also discovered that RNA must be present for this binding to occur.
• Understanding how the SMN protein interacts with other proteins may shed light on the molecular mechanisms through which SMN protein deficiency causes SMA.

 

Podium Presentation 6. Is SMA a Developmental Disease?

Federica Genovese, MSc ~ University of Edinburgh, Scotland, United Kingdom

Main Points:

• For individuals with the most severe types of SMA, treatment with one of the three FDA-approved disease modifying therapies before symptoms are present results in the best health outcomes.
• Genovese and her group found that in prenatal SMA mice, structures called primary cilia were shortened on a type of brain cell that is important for memory and learning. They also discovered that treating these cells in culture with risdiplam elongated the primary cilia.
• These findings may help explain why immediate treatment of babies born with severe SMA is necessary for optimal health outcomes.

Podium Presentation 7. Neurodevelopmental Disorders and Correlation with MRI Brain Abnormalities in Spain Muscular Atrophy Type 1

Rodrigo Holanda Mendonça MD, PhD ~ Hospital das Clinicas da Universidade de Sao Paulo, Brazil

Main Points:

• As more children born with SMA type 1 are treated early in life and living longer, researchers are learning more about how their brains develop as they age.
• In this study, Dr. Medonça and his research team used magnetic resonance imaging (MRI) to visualize the brain anatomy of a group of children with SMA, five of whom also had neurodevelopmental disorders. The group found that in children with SMA Type 1 and a neurodevelopmental disorder, brain anatomy may differ from that of children with SMA Type 1 who do not have a neurodevelopmental disorder.
• By characterizing the brain anatomy of children with Type 1 SMA as they age, researchers may begin to form an understanding of how SMA treatment may affect development.

 

Podium Presentation 8: Investigating Vulnerable Motor Neurons in Mouse Models of SMA

Laura Comley, PhD ~ University of Edinburg, Lothian, United Kingdom

 

Main Points:

• Motor neuron axons are nerve fibers that relay messages from the neurons to muscles. The health and function of motor neuron axons is impaired in people with SMA.
• Comley and her colleagues found that in a mouse model of SMA, motor neuron axons were lost as early as one day after birth in several muscle types. They also found that increasing SMN protein levels in these mice restored motor neuron axons in the less vulnerable type of muscle.
• These findings help explain why treatment timing is one variable that critically impacts outcomes of disease modifying therapies for SMA.

 

Podium Presentation 9: Investigating Combinatorial Therapeutics to Enhance Axon Regeneration in Mouse Models of SMA

Lyndsay Murray, PhD ~ University of Edinburg, Lothian, United Kingdom

Main Points:

• SMA causes progressive loss of the neuromuscular junctions where messages are passed from motor neurons to muscles. This communication breakdown results in the loss of muscle health and function.
• Murray and her group demonstrated that increasing SMN protein levels in SMA mice using a single compound can restore neuromuscular junctions, although the restoration can be incomplete and vary between muscle types. The researchers have also begun to test combinations of compounds that increase SMN protein levels in SMA mice. They want to determine if using more than one such compound can stimulate more complete neuromuscular junction recovery in more muscle types.
• Experiments like these may serve as a model for the future use of combination therapies to achieve the best possible health outcomes in people with SMA.

 

Podium Presentation 10: Charactering the Reversibility of Cellular and Molecular Defects of SMN-deficient Muscle

Elana Molotsky, PhD ~ Johns Hopkins University, MD, United States

Main Points:

• Prior research has established that SMN protein deficiency in motor neurons affected by SMA leads to muscle wasting, in part because neuromuscular communication is reduced. However, it is not known if SMN protein deficiency in the muscle itself also contributes to the loss of muscle health and function.
• To determine if SMN protein deficiency in the muscle itself negatively affects muscle cells, Dr. Molotsky and her colleagues used a special SMA mouse in which the SMN protein is only absent in muscle cells. They found that SMN protein deficiency exclusively in muscle cells caused muscle weakness, along with several types of intracellular changes, in SMA mice.
• These results suggest that SMN protein deficiency affects muscles directly as well as through motor neuron death. The findings support the idea that in the future, combination treatments including both a disease modifying therapy and a drug designed to support muscle cell function may lead to optimal health outcomes for people with SMA.

 

Podium Presentation 11: Β-adrenergic Signaling Is Impaired in Cardiomyocytes in A Mouse Model of Spinal Muscular Atrophy

Cecelia Mangione, BS ~ Uniformed Services University of the Health Sciences, MD, United States

Main Points:

• Research on the effects of SMN protein deficiency in SMA has thus far mainly focused on the spinal cord and muscles. However, because the SMN protein is expressed in tissues throughout the body, it is likely that other organs are affected by SMA.
• Mangione and her fellow researchers utilized SMA mice to learn more about how SMN protein deficiency may affect the cells of the heart. They were able to identify a specific signaling pathway, cAMP-PKA, that was disrupted in these cells, causing irregularities in the cardiac function of the SMA mice.
• Understanding the effects of SMN protein deficiency throughout the body may inform more comprehensive treatment and clinical care of people with SMA.

 

Podium Presentation 12: Liver SMN Restoration Rescues SMN2B/- Mouse Model of SMA: The Key to Rescue Whole-body Pathology?

Emma Sutton PhD ~ The Ottawa Hospital Research Institute, Ontario, Canada

Main Points:

• The SMN protein is expressed throughout the body, including in essential organs like the liver. It is not yet known whether SMN protein deficiency in SMA causes changes in the liver, and whether those changes in turn affect the health of the neuromuscular system.

• Using genetic and protein biochemistry techniques, Dr. Sutton’s group demonstrated that they were able to restore SMN protein levels exclusively in the liver of SMA mice with SMN protein deficiency. SMN protein restoration improved not only liver function but also partial recovery of neuromuscular function.
• These data suggest that elevating SMN protein levels throughout the body may have positive health effects beyond the neuromuscular system in people with SMA.

 

Podium Presentation 13: Stem Cell-derived Astrocytes Demonstrate Reduced Teneurin-4 Levels and Perisynaptic Astrocyte Process Defects in Spinal Muscular Atrophy

Emily Welby, PhD ~ Medical College of Wisconsin, United States

Main Points:

• The brain and spinal cord are made up of non-neuronal cells and neuronal cells. Non-neuronal brain cells, like those called “astrocytes,” support the structure and function of the more complex neuronal cells, like motor neurons.
• Welby’s research group used super resolution microscopy and biochemistry techniques to determine that the expression of a cell surface protein, TENNM4, is reduced in astrocytes derived from people with SMA. They also found that the reduction of TENM4 in turn decreased the number of filopodia found on astrocytes. Filopodia are important structures that project from astrocytes and help them locate and connect to motor neurons.
• Learning more about the effects of SMA on non-neuronal cells like astrocytes may contribute to researchers’ overall understanding of the disease process and inform a more comprehensive approach to developing treatments.