January 14, 2015

COLUMBUS, Ohio – Reversing a protein deficiency through gene therapy is effective in improving and stabilizing spinal muscular atrophy (SMA), a lethal childhood disorder modeled for the first time in a large animal, new research from The Ohio State University Wexner Medical Center and Nationwide Children's Hospital shows.

The findings are published online in the Annals of Neurology.

“We concluded that early treatment can have a major effect in SMA,” said lead author Arthur Burghes, a professor and researcher in the Department of Molecular and Cellular Biochemistry at Ohio State’s College of Medicine. “Before this study, there was no large animal model of SMA which could be used to predict outcomes in humans. In particular, piglets have a similar size to human babies and much closer physiology than mice, and are, therefore, more predictive of treatment outcomes in humans.” 

SMA is the leading genetic cause of infant death and affects motor neurons in the spinal cord.

SMA belongs to a group of hereditary diseases that cause weakness and wasting of the voluntary muscles in the arms and legs of infants and children. The disorder is caused by an abnormal or missing gene known as the survival motor neuron gene 1 (SMN1) and retention of the SMN2 gene. Both of these genes produce the essential protein, SMN, but SMN2 produces considerably less. With the reduced levels of this protein, motor neurons in the spinal cord degenerate and die. About 1 in 10,000 new births have SMA.  

Previous research has shown that restoring SMN will fix the underlying problem in SMA, and the major questions have been how to restore SMN and what effect it has when restored at different stages of the disease.

This study by researchers from Ohio State, Nationwide Children’s Hospital in Columbus, Ohio, and the University of Bern in Switzerland found that correction of SMN levels prior to symptoms of SMA results in complete correction of the disease. Correction of SMN levels when the pig has symptoms results in marked correction, with no further motor neuron loss. 

“We predict that early treatment will be successful in stabilization of SMA and the early intervention will allow for sprouting of the available motor neurons, which will result in improved muscle function,” said Burghes, whose research focuses on the molecular understanding of genetic neuromuscular disorders.

Burghes said the study found that, with early intervention, the remaining motor neurons are capable of sprouting and improving muscle function in the symptomatic pig. However, the number of motor neurons is not fully restored once they are lost, thus SMA can be stabilized at later time points but motor neurons that are lost cannot be restored.

“We also showed that the biomarkers of motor neuron function that can be used in both man and pig show a marked response to treatment, and will have predictive value in human clinical trial assessment,” said Burghes.

Ohio State’s Wexner Medical Center and Nationwide Children’s Hospital are performing a phase 1 clinical trial of gene therapy for SMA patients with the support of AveXis.  

Other researchers involved in the study include Sandra I. Duque, W. David Arnold, Xiaohui Li, Paul N. Porensky and Stephen J. Kolb from Ohio State; Philipp Odermatt and Daniel Schümperli from the Institute of Cell Biology at University of Bern, Switzerland; and Leah Schmelzer, Kathrin Meyer and Brian K. Kaspar from The Research Institute at Nationwide Children’s Hospital.

This work was funded by the Sophia’s Cure Foundation, SMA Europe and several grants from the National Institute of Neurological Disorders and Stroke.

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Media Contact: Eileen Scahill, Wexner Medical Center Media Relations, 614-293-3737, Eileen.Scahill@osumc.edu