SMA Scientists and Clinicians from Around the World Gather at the 27th Annual SMA Research & Clinical Care Meeting

1. Towards a Prenatal Therapy for Patients with Severe Spinal Muscular Atrophy – Preclinical Experiments in Mouse and Sheep Models

Beltran Borges, MD ~ University of California San Francisco

Main Points:

• Prenatal gene therapy for SMA may be an effective way to treat the disease before symptoms arise.
• In these experiments, Dr. Borges’s lab gathered information on the safest way to deliver prenatal SMA drugs by testing delivery techniques on pregnant mice and sheep.

2. Targeting Histone Acetylation Specifically to Smn2 Intron 6 Using a Crispr-Dead Cas9 Strategy Cooperates with Nusinersen to Promote Exon 7 Inclusion

Alberto Kornblihtt, PhD ~ Universidad de Buenos Aires

Main Points:

• The SMA drug nusinersen increases the amount of functional SMN protein produced by the SMN2 “back-up” gene.
• In a cell culture model, Dr. Kornblihtt's group used a technology called CRISPR to show that a molecule called VP64 can further increase the SMN-enhancing effect of nusinersen.

3. A Permanent Genetic Treatment for Spinal Muscular Atrophy Using Base Editors

Christiano Alves, PhD ~ Harvard and Massachusetts General Hospital

Main Points:

• The SMN2 gene produces lower levels of full-length SMN protein than the SMN1 gene because of a small difference in its DNA sequence.
• In cell cultures and mice, Dr. Alves and his colleagues tested different ways to correct or “edit” the difference in the SMN2 gene so that it will produce more full-length SMN protein.

4. Motor Unit Recovery Following AAV9-SMN Treatment in a Mouse Model of Spinal Muscular Atrophy

Laura Comley, PhD ~ University of Edinburgh, United Kingdom

Main Points:

• Treatment of SMA prevents the loss of projections called axons that motor neurons use to transmit messages.
• Using an SMA mouse model, Dr. Comley’s lab documented how increasing SMN protein levels with gene therapy partially restored motor neuron axons in some muscle types.

5. Survival Motor Neuron (SMN) Gene Therapy: Addressing Concerns of Sensorimotor Toxicity

Maria Balch, PhD ~ The Ohio State University Wexner Medical Center

Main Points:

• A previous research study published in 2021 found that a gene therapy similar to an FDA-approved SMA treatment for humans caused unwanted side effects in healthy mice.
• Through experiments using the FDA-approved treatment in SMA mice, Dr. Balch’s lab showed that the approved drug is unlikely to cause the types of side effects that occurred in the 2021 study.

6. Cerebellar Structural, Glial, and Neuronal Defects in a Mouse Model of Spinal Muscular Atrophy

Nicholas Cottam, BS ~ Delaware State University

Main Points:

• Prior research has suggested that SMA may affect the cerebellum, a region of the brain that coordinates balance and muscle movement.
• Using a range of techniques to quantify SMN protein levels throughout the SMA mouse brain, Mr. Cottom’s group found less SMN in the cerebellum than in other brain regions.

7. Cerebellar Pathology in Two Mouse Models for Spinal Muscular Atrophy

Florian Gerstner, MS/MA ~ Leipzig University, Germany

Main Points:

• Purkinje cells are specialized neurons in the cerebellar region of the brain that play a critical role in regulating muscle movement.
• In this study, researchers found that the size and biochemistry of Purkinje cells from two types of SMA mice were different from those in healthy mice.

8. Human Spinal Cord Organoid Models of Spinal Muscular Atrophy Exhibit Early Neurodevelopmental Defects

Natalia Rodriguez-Muela, PhD ~ German Center for Neurodegenerative Diseases/Technische Universitat Dresden/Max Planck Institute for Molecular Cell Biology and Genetics

Main Points:

• Early in brain development, pluripotent stem cells divide to create populations of several types of highly specialized nervous system cells.
• Using pluripotent stem cells derived from people with SMA, Dr. Rodriguez-Muela and her colleagues developed two different models for studying how SMA affects early neurodevelopment and motor neuron health.

9. One Ring to Rule Them All: Are Sm-Ring Associated Functions of SMN Central to the Development of SMA?

Anton Blatnik, PhD ~ The Ohio State University Wexner Medical Center

Main Points:

• SMN is one of the proteins that bind together to form Sm-rings, which transport RNA out of the nucleus to be translated into protein.
• Blatnik’s lab made genetic changes in cultured cells and SMA mice to learn more about how disrupting the function of SMN in Sm-rings contributes to SMA pathology.

10. Rapid Cytoplasmic Phase Separation of SMN in Response to Cellular Stress

Oliver Gruss, PhD ~ University of Bonn, Germany

Main Points:

• SMN protein can be found both diffused in the cytoplasm, a gelatinous fluid that fills the cell, and clustered inside structures called Cajal bodies within the nucleus.
• In these experiments, the researchers found that certain mechanical, cellular, and genetic changes can cause cytoplasmic SMN to condense into “stress granules.”

11. Mir34 Contributes to Spinal Muscular Atrophy (SMA) and AAV9-Mediated Delivery of Mir34a Ameliorates the Motor Deficits in SMA Mice

Tai-Heng Chen, PhD ~ Kaohsiung Medical University Hospital, Taiwan

Main Points:

• Biomarkers are needed to help healthcare providers make decisions about SMA diagnosis, prognosis, and treatment.
• To evaluate the RNA gene, MiR34, as an SMA biomarker, Dr. Chen’s group characterized levels of MiR34 in both SMA mice and people affected by SMA.

12. Nucleolin, an SMN-Interacting Protein, Binds WD-40 Domain of aCOP Through Its Dilysine Motif

Timra Gilson, PhD ~ Indiana University

Main Points:

• SMN interacts with two proteins called Nucleolin and aCOP to play a role in the assembly of ribosomes, which translate RNA into protein.
• Gilson’s group utilized biochemistry and genetics techniques to study how Nucleolin and aCOP interact with each other. They also created a transgenic mouse to learn more about the function of aCOP in motor neurons.

13. SMA Protective Modifier Plastin 3 Is Epigenetically Regulated by the Macrosatellite Dxz4 and the Transcription Regulator Chd4mir34

Brunhilde Wirth, PhD ~ University of Cologne, Germany

Main Points:

• The Plastin 3 gene (PLS3), located on the X-chromosome, is known as a “protective modifier” of autosomal recessive SMA because expression of PLS3 reduces disease severity.
• Wirth’s lab used advanced DNA sequencing and other techniques to identify factors that determine sex-dependent differences in how much PLS3 modifies SMA severity.

14. Mitigating Effects of a Synaptic Chaperone in Intermediate Smn2b/- Model Mice

Yoon Ra Her, PhD ~ Columbia University Medical Center

Main Points:

• Modifier genes can reduce SMA disease severity and are potential targets for SMA therapeutics.
• In this study, the researchers created a transgenic SMA mouse containing a variant of the gene Hspa. They found that the gene variant improved the health and motor function of the mice by stabilizing SMN levels.

15. Combinatorial Therapy Using a Zolgensma-Like Drug with Mifepristone to Target Whole-Body Pathologies in the Smn2b/- Mouse Model of SMA

Emma Sutton, PhD ~ Keele University, United Kingdom

Main Points:

• Prior research has found that the protein, Klf15, regulates the expression of some genes and is elevated in some tissues of SMA mice.
• Sutton showed that giving SMA mice a drug called mifepristone alone or in combination with gene therapy reduced levels of Klf15 in some tissues and improved the motor function and health.