Sheffield Institute for
Translational Neuroscience

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a form of motor neuron degeneration that usually starts during foetal development and is one of the most common genetic causes of infant death.

SMA is currently incurable and as yet there are no effective drug treatments available. SMA is caused by mutations in the survival motor neuron (SMN) gene resulting in reduced SMN protein levels. On the basis of the age of onset and the severity of the disease, four clinical subtypes have been described. The most severe form, type 1 SMA, is a devastating childhood condition also known as Werdnig-Hoffmann disease or “floppy baby syndrome” which is
generally fatal by three years of age.

SMN replacement gene therapy for SMA

Professor Azzouz’s team is in the final stages of developing a gene therapy aimed at restoring the missing SMN protein. This therapeutic approach was first developed and proven by Azzouz and colleagues to ameliorate the disease phenotype in animal models. The team has now optimised their carrier system using a self-complementary adeno-associated virus (scAAV9) that crosses the blood brain barrier and allows fast, robust and long-lasting gene transfer.

The group has demonstrated that a single intravenous injection of scAAV9-SMN rescues the lethal phenotype in the established SMNΔ7 mouse model of SMA and leads to a robust increase in survival of the SMNΔ7 mice  from 14 days to more than 300 days. The SMN replacement gene therapy has received orphan drug status from the European Medicines Agency (EMA), and the team is now developing the therapy towards Phase I clinical trials in humans. Plans are in place to finalise safety and toxicology studies to advance the therapy to a first-into-human trial.

Understanding the pathogenesis of SMA

SMN plays a crucial role in pre-mRNA splicing and axonal transport of mRNAs. How exactly SMN deficiency leads to the loss of motor neurons is still unclear. The team is currently investigating gene expression changes using next generation RNA sequencing (RNAseq), as well as axonal transport defects using live cell-imaging to shed light on the disease mechanisms.

Neuroprotection strategies for SMA

The actin-binding protein Plastin 3 (PLS3) has been reported as a modifier for SMA that improves axonal outgrowth in SMN-deficient zebrafish when overexpressed. PLS3 is now being evaluated in the SMA mouse model as a candidate for a neuroprotective gene therapy.